Certain 4-aminomethyl-2-substituted imidazole derivatives and 2-aminomethyl-4-substituted imidazole derivatives; new classes of dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula:  
                 
 
     wherein R 1  represents optionally substituted aryl, heteroaryl, arylalkyl, or cycloalkyl groups; X, Z, and Y are optionally substituted nitrogen or carbon atoms; R 3  and R 4  are organic or inorganic substitutents which may together form ring structutes; m is zero, one or two; and R 5  and R 6  are are organic or inorganic substituents;  
     and the pharmaceutically acceptable addition salts thereof,  
     which compounds are highly selective partial agonists or antagonists at brain dopamine receptor subtypes or prodrugs thereof and are useful in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism.

[0001] This application is a continuation in part of U.S. patentapplication Ser. No. 08/081,317, filed Jun. 25, 1993, which is acontinuation-in-part of U.S. patent application Ser. No. 07/635,256,filed Dec. 28, 1990.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to certain 4-aminomethyl-2-substitutedimidazole and 2-aminomethyl-4-substituted derivatives which selectivelybind to brain dopamine receptor subtypes. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating affective disorderssuch as schizophrenia and depression as well as certain movementdisorders such as Parkinsonism. Furthermore, compounds of this inventionmay be useful in treating the extrapyramidyl side effects associatedwith the use of conventional neuroleptic agents. The interaction ofthese aminomethylimidazole derivatives of the invention with dopaminereceptor subtypes is described. This interaction results in thepharmacological activities of these compounds.

[0004] 2. Description of the Related Art

[0005] Schizophrenia or psychosis is a term used to describe a group ofillnesses of unknown origin which affect approximately 2.5 millionpeople in the United States. These disorders of the brain arecharacterized by a variety of symptoms which are classified as positivesymptoms (disordered thought, hallucinations and delusions) and negativesymptoms (social withdrawal and unresponsiveness). These disorders havean age of onset in adolescence or early adulthood and persist for manyyears. The disorders tend to become more severe during the patient'slifetime and can result in prolonged institutionalization. In the UnitedStates today, approximately 40% of all hospitalized psychiatric patientssuffer from schizophrenia.

[0006] During the 1950's physicians demonstrated that they couldsucessfully treat psychotic patients with medications calledneuroleptics; this classification of antipsychotic medication was basedlargely on the activating (neuroleptic) properties of the nervous systemby these drugs. Subsequently, neuroleptic agents were shown to increasethe concentrations of dopamine metabolites in the brain suggestingaltered neuronal firing of the dopamine system. Additional evidenceindicated that dopamine could increase the activity of adenylate cyclasein the corpus striatum, an effect reversed by neuroleptic agents. Thus,cumulative evidence from these and later experiments strongly suggestedthat the neurotransmitter dopamine was involved in schizophrenia.

[0007] One of the major actions of antipsychotic medication is theblockade of dopamine receptors in brain. Several dopamine systems appearto exist in the brain and at least five classes of dopamine receptorsappear to mediate the actions of this transmitter. These dopaminereceptors differ in their pharmacological specificity and wereoriginally classified upon these differences in the pharmacology ofdifferent chemical series. Butyrophenones, containing many potentantipsychotic drugs were quite weak at the dopamine receptor thatactivated adenylate cyclase (now known as a D1 dopamine receptor). Incontrast, they labelled other dopamine receptors (called D2 receptors)in the subnanomolar range and a third type D3 in the nanomolar range.Two additional receptor subtypes have also been identified. D5 which issomewhat similar to D1 receptor type and D4 which is closely related toD3 and D2 receptor types. Phenothiazines possess nanomolar affinity forall three types of dopamine receptors. Other drugs have been developedwith great specificity for the D1 subtype receptor and for the D2subtype receptor.

[0008] A certain group of drugs (such as sulpiride and clozapine) havebeen developed with a lesser incidence of extrapyramidal side effectsthan classical neuroleptics. In addition, there is some indication thatthey may be more beneficial in treating negative symptoms in somepatients. Drugs of this class are often referred to as atypicalantipsychotic agents. Since all D2 blockers do not possess a similarprofile, hypotheses underlying the differences have been investigated.The major differences have been in the anticholinergic actions of theneuroleptics as well as the possibility that the dopamine receptors maydiffer in motor areas from those in the limbic areas thought to mediatethe antipsychotic responses. The existence of the D3, D4 and D5 andother as yet undiscovered dopamine receptors may contribute to thisprofile. Some of the atypical compounds possess similar activity at D2,D3 and D4 receptors. The examples of this patent fall into this generalclass of molecules.

[0009] Using molecular biological techniques it has been possible toclone cDNAs coding for each of the pharmacologically defined receptors.There are at least two forms of D1-type receptors which have beenclassified as D1 and D5, and two forms of D2-type receptors, classifiednow as D2 and D4 dopamine receptors. In addition, there is at least oneform of D3 dopamine receptor. Examples from the substitutedaminomethylimidazole series of this patent possess differentialaffinities for each receptor subtype.

[0010] Schizophrenia is characterized by a variety of cognitivedysfunctions; schizophrenic patients perform less well than other groupson most cognitive or attentional tasks. The positive and negativesymptom dimensions of schizophrenia are also associated with distinctcognitive deficits. In general, positive symptoms (disordered thoughtprocesses, hallucinations and decisions) are related to auditoryprocessing imairments including deficits in verbal memory and languagecomprehension. Negative symptoms (social withdrawal andunresponsiveness) are related more to visual/motor dysfunctionsincluding poorer performance on visual memory, motor speed and dexteritytasks.

[0011] These disorders have an age of onset in adolescence or earlyadulthood and persist for many years. The interaction of frontal andsepto-hippocampal brain systems, and failures of information processingand self monitoring have been theorized as the basis of positivesymptoms. Negative symptoms are thought to arise from abnormalities inthe interactions of frontal and striatal systems. Since cognitivedisturbances are present in most of the patients diagnosed as havingschizophrenia, it has been theorized that to understand the pathogenesisand etiology of schizophrenia one must understand the basic dysfunctionof the cognitive disorder.

[0012] The cognitive disturbances found in schizophrenia include, butare not limited to, various verbal and visual memory deficits. There arevarious neurocognitive tasks for both animals and humans that have beendeveloped to assess memory deficits, as well as memory enhancements, ofvarious treatments. Many of the neurocognitive behavioral tasks aremodulated or mediated by eural activity within the hippocampal brainsystem noted above.

[0013] Drug substances that interact with the hippocampus are capable ofmodulating memory in animals. Certain memory paradigms employed inanimals have construct and predictive validity for memory assessment inhumans. In animals (rodents), paradigms such as the Step-Down PassiveAvoidance Task assay or the Spatial Water Maze Task assay reliablydetect deficits produced by certain drugs in humans. For example,commonly prescribed benzodiazepine anxiolytics and sedative hypnoticsare known to produce memory impairment in humans, including varyingdegrees of anterograde amnesia (depending on the exact drug). In thestep-down passive avoidance paradigm, these very same drugs disrupt thememory of animals given the compounds during the information acquisitionor processing period. Likewise, benzodiazepines disrupt informationprocessing and memories in the spatial water maze task in rodents. Thus,these animal models can be used to predict the memory impairing effectsof certain compounds in humans. Conversely, these same animal models canpredict the memory improving or enhancing effects of compounds inhumans. Although fewer in number, drugs that improve memory in humans(e.g., Nootroprice, Beta carbolines) produce memory enhancing effects inrats in these models. Therefore, the spatial water maze and step-downpassive avoidance paradigms in rodents are useful in predicting memoryimpairing and memory enhancing effects of test compounds in humans.

SUMMARY OF THE INVENTION

[0014] This invention provides novel compounds of Formula I whichinteract with dopamine receptor subtypes.

[0015] The invention provides pharmaceutical compositions comprisingcompounds of Formula I. The invention also provides compounds useful intreating affective disorders such as schizophrenia and depression aswell as certain movement disorders such as Parkinsonism. Furthermorecompounds of this invention may be useful in treating the extrapyramidylside effects associated with the use of conventional neuroleptic agents.Since dopamine D3 and D4 receptor subtypes are particularly concentratedin the limbic system (Taubes, Science (1994) 265 1034) which controlscognition and emotion, compounds which interract with these receptorsmay have utility in the treatment of cognitive disorders. Such disordersmay be the cognitive deficits which are a significant component of thenegative symptoms (social withdrawal, and unresponsiveness) ofschizophrenia. Other disorders involving memory impairment or attentiondeficit disorders may also be treated with some of the compounds of thisinvention that interact specifically with dopamine D3 and/or D4 receptorsubtypes. Accordingly, the invention is directed to a compound ofFormula I:

[0016] where

[0017] R₁ is: aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl;unsubstituted or substituted by up to 3 substituents which may be thesame or different and represent hydrogen, halogen, trifluoromethyl,cyano, straight or branched chain lower alkyl having 1-6 carbon atoms,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms, orSO₂R₉ where R₉ is NH₂ or NHCH₃;

[0018] X is: N or NR₂ where R₂ is hydrogen or straight or branched chainlower alkyl having 1-6 carbon atoms.

[0019] Y is: N or CR₃

[0020] Z is: CR₃ or N

[0021] provided that Y and Z are not both CR₃; and

[0022] provided that Y and Z are not both N;

[0023] R₃ is: hydrogen, lower alkyl, halogen, hydroxy lower alkyl orphenyl unsubstituted or substituted by up to three substituents whichmay be the same or different and represent hydrogen, halogen,trifluoromethyl, cyano, sulfonamido, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

[0024] R₄ is: hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms, or R₃ and R₄ together may represent —(CH₂)n₁— where n₁is 2, 3 or 4; or R₂ and R₄ together may represent —(CH₂)n₂— where n₂ is2, 3 or 4.

[0025] m is: zero, one or two

[0026] R₅ and R₆ are the same or different and represent hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms, aryl,straight or branched chain lower alkyl having 1-6 carbon atoms or R₂ andR₅ together may represent —(CH₂)n₃— where n₃ is 2 or 3; or

[0027] NR₅R₆ together represent: 2-(1,2,3,4-tetrahydroisoquinolinyl),either unsubstituted or mono or disubstituted with halogen, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0028] NR₅R₆ represents:

[0029] where

[0030] R₇ is phenyl, benzyl or phenethyl with the phenyl ringunsubstituted or substituted with up to three substituents which may bethe same or different and represent hydrogen, halogen, trifluoromethyl,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0031] NR₅R₆ represents:

[0032] where

[0033] p is 1, 2, or 3;

[0034] W is N or CH; and

[0035] W is N and R₈ is hydrogen, phenyl, pyridyl or pyrimidinyl,unsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; or

[0036] W is CH and R₈ is optionally substituted phenyl or an arylalkylgroup such as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

[0037] These compounds are highly selective partial agonists orantagonists at brain dopamine receptor subtypes or prodrugs thereof andare useful in the diagnosis and treatment of affective disorders such asschizophrenia and depression as well as certain movement disorders suchas Parkinsonism. Furthermore, compounds of this invention may be usefulin treating the extrapyramidyl side effects associated with the use ofconventional neuroleptic agents. Furthermore, compounds of thisinvention may have utility in the treatment of cognitive disorders. Suchdisorders may be the cognitive deficits which are a significantcomponent of the negative symptoms (social withdrawal, andunresponsiveness) of schizophrenia or other disorders involving memoryimpairment or attention deficit disorders.

[0038] The compounds of the invention, such as, for example,2-Phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (compound 23),2-Phenyl-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 24), and2-Phenyl-4(5)-[(4-phenyl-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 45), are antagonists binding to dopamine D4receptors in both the rat and human hippocampus.

[0039] As noted above, the hippocampus is associated with bothschizophrenia, and general memory processes in humans. In rodents,compound 23 produces memory enhancing effects in both the step-downpassive avoidance assay as well as in the spatial water maze assay.Without being bound by a particular theory, it is believed that the D₄receptors located in the hippocampus mediate the memory enhancingeffects of the compounds of the invention. Therefore, since (1) compound23 is active in animal models that are predictive of cognitionenhancement, and specifically enhancement of memory and learning, and(2) compound 23 binds to D₄ receptors in the hippocampus, the D₄ classof dopamine antagonists, including the compounds of the invention, areuseful for enhancing memory in humans.

[0040] Thus, the invention further provides methods for enhancingcognition, and specifically learning and memory, in mammals. Thesemethods comprise administering to a mammal such as a human a compound ofthe invention in an amount effective to enhance cognition.

BRIEF DESCRIPTION OF THE DRAWING

[0041]FIGS. 1, 2, and 3 show representative substitutedaminomethylimidazoles of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0042] In addition to compounds of general formula I described above,the present invention further encompasses compounds of Formula II:

[0043] where

[0044] R₁, X, Y, Z, m are as defined above for Formula I;

[0045] R₃ is hydrogen, halogen, straight or branched chain lower alkylhaving 1-6 carbon atoms;

[0046] R₄ is hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms, or, where Z is CR₃, R₃ and R₄ together may represent—(CH₂)n₁— where n₁ is 2, 3 or 4; or R₂ and R₄ together may represent—(CH₂)n₂— where n₂ is 2, 3 or 4.

[0047] R₂ and R₅ together may represent —(CH₂)n₃— where n₃ is 2 or 3;

[0048] R6 is hydrogen, straight or branched chain lower alkyl, phenyl orarylalkyl; or

[0049] NR₅R₆ represents:

[0050] where

[0051] R₇ is as defined for Formula I.

[0052] NR₅R₆ represents:

[0053] where

[0054] p, and is 1, 2, or 3;

[0055] W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted ormono or disubstituted with halogen, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

[0056] W is CH and R₈ is optionally substituted phenyl or an arylalkylgroup such as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

[0057] Preferred compounds according to Formula I include those where Zis CR₃ and R₃ and R₄ together form a 5 or 6-membered ring; R₁ issubstituted or unsubstituted phenyl; X is: N; Y is: N; and R₅ and R₆represents:

[0058] where

[0059] p is 2; and

[0060] W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted ormono or disubstituted with halogen, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

[0061] W is CH and R₈ is optionally substituted phenyl or an arylalkylgroup such as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

[0062] Preferred compounds according to Formula II are those where R₁ isphenyl optionally substituted in the 4-position with halogen or alkyl, Yand X are nitrogen, Z is CH, R₄ is hydrogen, m is 0, and NR₄R₅represents 4-substituted piperazin-1-yl or 4-substituted piperidin-1-yl.The piperazinyl or piperidinyl groups are substituted in the 4-positionwith pyridyl or pyrimidinyl, or phenyl or benzyl each of which isoptionally substituted, preferably in the 4-position, with halogen,alkyl, or alkoxy. The preferred piperidinyl groups are optionallysubstituted in the 3-position with alkyl, and more preferably, methyl,groups. Particularly preferred R₁ groups are 4-methylphenyl and4-halophenyl groups.

[0063] The present invention also encompasses compounds of Formula IIA:

[0064] where

[0065] R₁ is: aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl;unsubstituted or substituted by up to 3 substituents which may be thesame or different and represent hydrogen, halogen, trifluoromethyl,cyano, straight or branched chain lower alkyl having 1-6 carbon atoms,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms, orSO₂R₉ where R₉ is NH₂ or NHCH₃;

[0066] R₂ is hydrogen or alkyl;

[0067] R₃ is: hydrogen, lower alkyl, halogen, hydroxy lower alkyl, orphenyl unsubstituted or substituted by up to three substituentsindependently selected from hydrogen, halogen, trifluoromethyl, cyano,sulfonamido, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

[0068] R₄ is: hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms, or R₃ and R₄ together may represent —(CH₂)n₁— where n₁is 2, 3 or 4; or R₂ and R₄ together may represent —(CH₂)n₂— where n₂ is2, 3 or 4.

[0069] m is: zero, one or two

[0070] R₅ and R₆ are the same or different and represent hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms, aryl,straight or branched chain lower alkyl having 1-6 carbon atoms or R₂ andR₅ together may represent —(CH₂)n₃— where n₃ is 2 or 3; or

[0071] NR₅R₆ together represent: 2-(1,2,3,4-tetrahydroisoquinolinyl),either unsubstituted or mono or disubstituted with halogen, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0072] NR₅R₆ represents:

[0073] where

[0074] R₇ is phenyl, benzyl or phenethyl with the phenyl ringunsubstituted or substituted with up to three substituents which may bethe same or different and represent hydrogen, halogen, trifluoromethyl,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0075] R₅R₆ represents:

[0076] where

[0077] p is 1, 2, or 3; and

[0078] W is N and R₈ is hydrogen, phenyl, pyridyl or pyrimidinyl,unsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; or

[0079] W is CH and R₈ is optionally substituted phenyl, optionallysubstituted benzoyl, or an arylalkyl group such as, for example,phenylalkyl where the phenyl ring may be substituted with up to threesubstituents independently selected from hydrogen, halogen,trifluoromethyl, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms.

[0080] Preferred compounds of Formula IIA are those where R₁ isoptionally substituted phenyl; R₂ and R₄ are hydrogen; and R₅ is alkyland R₆ is arylalkyl, preferably optionally substituted, and morepreferably unsubstituted, benzyl; or NR₅R₆ is:

[0081] where p, W, and R₈ are as defined above for Formula I.

[0082] Particularly preferred compounds of Formula IIA are those whereR₁ is optionally substituted phenyl; R₂ and R₄ are hydrogen; R₅ is alkyland R₆ is arylalkyl, preferably optionally substitued, and morepreferably unsubstituted, benzyl; or NR₅R₆ is:

[0083] where

[0084] p, is 2;

[0085] W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted ormono or disubstituted with halogen, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

[0086] Particularly preferred compounds of Formula IIA are those whereR₁ is optionally substituted phenyl; R₂ and R₄ are hydrogen; R₃ ishydrogen; R₅ is alkyl and R₆ is arylalkyl, preferably optionallysubstituted, and more preferably unsubstituted, benzyl; or NR₅R₆ is:

[0087] where

[0088] p, is 2;

[0089] W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted ormono or disubstituted with halogen, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

[0090] Other particularly preferred compounds of Formula IIA are thosewhere R₁ is phenyl; R₂ and R₄ are hydrogen; R₃ is hydrogen; and NR₅R₆is:

[0091] where

[0092] p, is 2; and

[0093] W is CH and R₈ is optionally halogenated or alkoxylated phenyl oran arylalkyl group such as, for example, phenylalkyl where the phenylring is optionally substituted with up to three substituentsindependently selected from hydrogen, halogen, or straight or branchedchain lower alkoxy having 1-6 carbon atoms.

[0094] The present invention also encompasses compounds of Formula III:

[0095] where

[0096] R₁ is aryl, heteroaryl, or naphthyl; unsubstituted or substitutedby up to three substituents which may be the same or different andrepresent hydrogen, halogen, trifluoromethyl, cyano, straight orbranched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight orbranched chain lower alkyl having 1-6 carbon atoms, straight or branchedchain lower alkoxy having 1-6 carbon atoms, or SO₂R₉ where R₉ is NH₂ orNHCH₃;

[0097] X, Y, Z, m, are as defined above for Formula I;

[0098] R₃ is hydrogen, halogen, straight or branched chain lower alkylhaving 1-6 carbon atoms;

[0099] R₄ is hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms, or, when Z is CR₃, R₃ and R₄ together may represent—(CH₂)n₁— where n₁ is 2, 3 or 4;

[0100] NR₅R₆ represents:

[0101] where

[0102] R₇ is as defined above for Formula I; or

[0103] NR₅R₆ represents:

[0104] where

[0105] p, and is 1, 2, or 3;

[0106] W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted ormono or disubstituted with halogen, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

[0107] W is CH and R₈ is optionally substituted phenyl or an arylalkylgroup such as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

[0108] In addition, the present invention encompasses compounds ofFormula IV:

[0109] where

[0110] R₁ is phenyl or naphthyl, each of which may be substituted by upto three substituents independently selected from hydrogen, halogen,trifluoromethyl, cyano, straight or branched chain lower alkyl having1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain tower alkoxy having 1-6carbon atoms, or SO₂R₉ where R₉ is NH₂ or NHCH₃.

[0111] X, Y, Z, are as defined above for Formula I,

[0112] R₃ is hydrogen, halogen, straight or branched chain lower alkylhaving 1-6 carbon atoms;

[0113] R₄ is hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms;

[0114] m is zero;

[0115] NR₅R₆ represents:

[0116] where

[0117] R₇ is as defined above for Formula I; or

[0118] NR₅R₆ represents:

[0119] where

[0120] p, and is 1, 2, or 3;

[0121] W is N and R₈ is phenyl, pyridyl or pyrimidinyl, unsubstituted ormono or disubstituted with halogen, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or

[0122] W is CH and R₈ is optionally substituted phenyl or an arylalkylgroup such as, for example, phenylalkyl where the phenyl ring may besubstituted with up to three substituents independently selected fromhydrogen, halogen, trifluoromethyl, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.

[0123] The invention further encompasses compounds of Formula V:

[0124] and the pharmaceutically acceptable non-toxic salts thereofwherein

[0125] R₁ and T are the same or different and represent hydrogen,halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms;

[0126] M is

[0127] where

[0128] R₂ is hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms, or R₁ and R₂ together may represent —(CH₂)n₁ where n₁is 1, 2, or 3;

[0129] X and Z are the same or different and represent hydrogen,halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, straight or branched chain lower alkoxy having 1-6 carbonatoms or SO₂R₆ where R₆ is straight or branched chain lower alkyl having1-6 carbon atoms;

[0130] Y is hydrogen, halogen, amino, or straight or branched chainlower alkyl having 1-6 carbon atoms;

[0131] R₃ is hydrogen or, straight or branched chain lower alkyl having1-6 carbon atoms, or R₃ and R₄ together may represent —(CH₂)n₂— where n₂is 3 or 4; and

[0132] R₄ and R₅ are the same or different and represent hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms, orphenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain alkyl having 1-6 carbon atoms; or

[0133] R₂ and R₅ together may represent —(CH₂)n₃— where n₃ is 2 or 3; or

[0134] NR₄R₅ represents 2-(1,2,3,4-tetrahydroisoquinolinyl), or2-(1,2,3,4-tetrahydroiso-quinolinyl) mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0135] where

[0136] W is N or CH; and

[0137] R₇ is hydrogen, phenyl, pyridyl or pyrimidinyl, or phenyl,pyridyl or pyrimidinyl, each of which is mono or disubstituted withhalogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or

[0138] W—R₇ is oxygen or sulfur; and

[0139] n is 1, 2, or 3.

[0140] The present invention further encompasses compounds of FormulaVI:

[0141] wherein

[0142] R₁ is hydrogen, halogen, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

[0143] M is

[0144] where

[0145] R₂ is hydrogen or, straight or branched chain lower alkyl having1-6 carbon atoms, or R₁ and R₂ together may represent —(CH₂)n₁ where n₁is 1, 2, or 3;

[0146] X is hydrogen, halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms or SO₂R₆ where R₆ is straight or branched chainlower alkyl having 1-6 carbon atoms;

[0147] R₃ is hydrogen or straight or branched chain lower alkyl having1-6 carbon atoms, or R₃ and R₄ together may represent —(CH₂)n₂— where n₂is 3 or 4; and

[0148] R₄ and R₅ are the same or different and represent hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms,phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or

[0149] R₂ and R₅ together may represent —(CH₂)n₃— where n₃ is 2 or 3; or

[0150] NR₄R₅ represents 2-(1,2,3,4-tetrahydroisoquinolinyl) or2-(1,2,3,4-tetrahydroisoquinolinyl) mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0151] where

[0152] W is N or CH;

[0153] R₇ is hydrogen, phenyl, pyridyl or pyrimidinyl, or phenyl,pyridyl or pyrimidinyl, each of which may be mono or disubstituted withhalogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or

[0154] W—R₇ is oxygen or sulfur; and

[0155] n is 1, 2, or 3.

[0156] The present invention also encompases compounds of Formula VII:

[0157] wherein

[0158] R₁ is hydrogen, halogen, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms;

[0159] M is

[0160] where

[0161] R₂ is hydrogen, or straight or branched chain lower alkyl having1-6 carbon atoms, or R₁ and R₂ together may represent —(CH₂)n₁ where n₁is 1, 2, or 3;

[0162] R₃ is hydrogen, or straight or branched chain lower alkyl having1-6 carbon atoms, or R₃ and R₄ together may represent —(CH₂)n₂— where n₂is 3 or 4; or

[0163] R₄ and R₅ are the same or different and represent hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms, arylstraight or branched chain lower alkyl having 1-6 carbon atoms or R₂ andR₅ together may represent —(CH₂)n₃— where n₃ is 2 or 3; or

[0164] NR₄R₅ represents 2-(1,2,3,4-tetrahydroisoquinolinyl), or2-(1,2,3,4-tetrahydroiso-quinolinyl) mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0165] where

[0166] W is N or CH;

[0167] R₇ is hydrogen, phenyl, pyridyl or pyrimidinyl; or phenyl,pyridyl or pyrimidinyl mono or disubstituted with halogen, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0168] W—R₇ is oxygen or sulfur; and

[0169] n is 1, 2, or 3.

[0170] In addition, the present invention encompasses compounds ofFormula VII:

[0171] wherein

[0172] M is

[0173] where

[0174] R₂ is hydrogen or, straight or branched chain lower alkyl having1-6 carbon atoms, or R₁ and R₂ together may represent —(CH₂)n₁ where n₁is 1, 2, or 3;

[0175] X is hydrogen, halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms, or SO₂R₆ where R₆ is straight or branched chainlower alkyl having 1-6 carbon atoms;

[0176] R₃ is hydrogen, or straight or branched chain lower alkyl having1-6 carbon atoms, or R₃ and R₄ together may represent —(CH₂)n₂— where n₂is 3 or 4; and

[0177] R₄ and R₅ are the same or different and represent hydrogen,straight or branched chain lower alkyl having 1-6 carbon atoms,phenylalkyl or pyridylalkyl where each alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; or

[0178] R₂ and R₅ together may represent —(CH₂)n₃— where n₃ is 2 or 3; or

[0179] NR₄R₅ represents 2-(1,2,3,4-tetrahydroisoquinolinyl), or2-(1,2,3,4-tetrahydroiso-quinolinyl) mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0180] where

[0181] W is N or CH;

[0182] R₇ is hydrogen, phenyl, pyridyl or pyrimidinyl, or hydrogen,phenyl, pyridyl or pyrimidinyl, mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or

[0183] W—R₇ is oxygen or sulfur, and

[0184] n is 1, 2, or 3.

[0185] The invention also provides compounds of Formula IX:

[0186] where

[0187] X represents a hydrogen or halogen;

[0188] R_(a) and R_(b) are the same or different and represent hydrogenor alkoxy; and

[0189] NR₄R₅ represents 4-(substituted or unsubstitutedphenyl)piperazin-1-yl or 4-phenyl-piperidin-1-yl, where the phenyl groupmay be substituted with hydrogen, alkyl, or alkoxy.

[0190] The invention also provides compounds of Formula X:

[0191] where

[0192] X represents a hydrogen or halogen;

[0193] R represents hydrogen or alkyl;

[0194] R_(a) and R_(b) are the same or different and represent hydrogenor alkoxy; and

[0195] A and B are the same or different and represent hydrogen or(4-(2-pyrimidinyl)piperazin-1-yl)methyl.

[0196] Preferred compounds of Formula X are those where R is hydrogen ormethyl and X, R_(a) and R_(b) are hydrogen. Particularly preferredcompounds of Formula X are those where R is hydrogen or methyl, X, R_(a)and R_(b) are hydrogen, and A and B are different and represent hydrogenor (4-(2-pyrimidinyl)piperazin-1-yl)methyl.

[0197] Also within the scope of the invention are compounds of FormulaXI:

[0198] where

[0199] X represents a hydrogen or halogen;

[0200] R represents hydrogen or alkyl;

[0201] R_(a) and R_(b) are the same or different and represent hydrogenor alkoxy, and

[0202] R_(c) is a group of the formula:

[0203] where

[0204] W is N or CH;

[0205] R represents alkyl;

[0206] Rd represents pyridyl, pyrimidinyl, phenylalkyl, or phenyloptionally substituted with halogen, alkyl or alkoxy; and

[0207] R_(e) is alkyl.

[0208] Preferred compounds of Formula XI are those where X, R_(a),R_(b), and R_(e) are hydrogen and R_(c) is a 4substituted piperazin-1-ylor piperidin-1-yl group. Particularly preferred compounds of Formula XIarc those where the 4-substituted piperazin-1-yl or piperidin-1-ylgroups are substituted with optionally substituted phenyl, phenylalkyl,2-pyridyl or 2-pyrimidinyl groups. Other preferred compounds of formulaXI are those where X, R_(a), R_(b), and R_(e) are hydrogen, R_(e) ismethyl and R_(c) is piperazin-1-yl or piperidin-1-yl each of which issubstituted in the 4-position with benzyl, pyridyl or pyrimidinyl.

[0209] The invention also provides compounds of Formula XII:

[0210] where

[0211] W is N or CH;

[0212] R_(f) is halogen or alkyl;

[0213] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

[0214] Preferred compounds of Formula XII are those where R_(f) ishalogen or methyl, W is nitrogen, and R_(d) is pyridyl, pyrimidinyl, orbenzyl. Particularly preferred compounds of Formula XII are those whereR_(f) is halogen or methyl, W is nitrogen, and R_(d) is pyrimidinyl.

[0215] The invention further provides compounds of Formula XIII:

[0216] where

[0217] W is N or CH;

[0218] R_(f) is alkyl; and

[0219] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

[0220] Preferred compounds of Formula XIII are those where R_(f) ismethyl, W is nitrogen, and R_(d) is pyridyl, pyrimidinyl, or benzyl.Particularly preferred compounds of Formula XIII are those where R_(f)is methyl, W is nitrogen. and R_(d) is pyrimidinyl

[0221] The invention further provides compounds of Formula XIV:

[0222] where

[0223] Ar is 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-pyrazinyl,2-thienyl, or 2-quinolinyl,

[0224] W is N or CH;

[0225] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

[0226] Preferred compounds of Formula XIV are those where W is CH, andR_(d) is pyridyl, pyrimidinyl, or benzyl.

[0227] The invention further provides compounds of Formula XV:

[0228] where

[0229] Ar is 1- or 2-naphthyl, phenyl or phenyl mono-, di- ortrisubstituted with alkyl, alkoxy or halogen,

[0230] W is N or CH;

[0231] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

[0232] Preferred compounds of Formula XV are those where Ar is phenyl, Wis CH, and R_(d) is pyridyl, pyrimidinyl, or benzyl.

[0233] The invention further provides compounds of Formula XVI:

[0234] where

[0235] X represents a hydrogen or halogen;

[0236] R_(a) and R_(b) are the same or different and represent hydrogenor alkoxy;

[0237] W is N or CH;

[0238] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, hydroxy, alkyl or alkoxy.

[0239] Preferred compounds of Formula XVI are those where X, R_(a) andR_(b) are hydrogen, W is CH, and R_(d) is pyridyl, pyrimidinyl, orbenzyl.

[0240] The invention further provides compounds of Formula XVII:

[0241] where

[0242] X represents a hydrogen or halogen;

[0243] R_(a) and R_(b) are the same or different and represent hydrogenor alkoxy;

[0244] W is N or CH;

[0245] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, hydroxy, alkyl or alkoxy.

[0246] Preferred compounds of Formula XVII are those where X, R_(a) andR_(b) are hydrogen, W is N, and R_(d) is pyridyl, pyrimidinyl, orbenzyl.

[0247] The invention further provides compounds of Formula XVIII:

[0248] where

[0249] m is 0, 1 or 2;

[0250] X represents a hydrogen or halogen;

[0251] R_(a) and R_(b) are the same or different and represent hydrogenor alkoxy,

[0252] W is N or CH;

[0253] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, hydroxy, alkyl or alkoxy.

[0254] Preferred compounds of Formula XVIII are those where X, R_(a) andR_(b) are hydrogen, W is N, and R_(d) is pyridyl, pyrimidinyl, or benzyl

[0255] The invention further provides compounds of Formula XIX:

[0256] where

[0257] m is 0, 1 or 2;

[0258] X represents a hydrogen or halogen;

[0259] R_(a) and R_(b) are the same or different and represent hydrogenor alkoxy;

[0260] W is N or CH;

[0261] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, hydroxy, alkyl or alkoxy.

[0262] Preferred compounds of Formula XIX are those where X, R_(a) andR_(b) are hydrogen, W is N, and R_(d) is pyridyl, pyrimidinyl, orbenzyl. Other preferred compounds of formula XIX are those where X,R_(a) and R_(b) are hydrogen, W is CH, and R_(d) is phenyl substitutedwith halogen and/or hydroxy.

[0263] The invention also provides compounds of Formula XX:

[0264] where

[0265] R_(a) is alkyl;

[0266] W is N or CH;

[0267] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

[0268] Preferred compounds of Formula XX are those where W is nitrogen,R_(a) is hydrogen or methyl, and R_(d) is pyridyl, pyrimidinyl, orbenzyl. Other preferred compounds according to Formula XX are thosewhere W is CH, R_(a) is hydrogen or methyl, and R_(d) is pyridyl,pyrimidinyl, or benzyl.

[0269] The invention also provides compounds of Formula XXI:

[0270] where

[0271] W is N or CH; and

[0272] R_(d) is pyridyl, pyrimidinyl, phenylalkyl, or phenyl optionallysubstituted with halogen, alkyl or alkoxy.

[0273] Preferred compounds of Formula XXI are those where W is nitrogen,R_(a) is hydrogen or methyl, and R_(d) is pyridyl, pyrimidinyl, orbenzyl. Other preferred compounds according to Formula XXI are thosewhere W is CH, R_(a) is hydrogen or methyl, and R_(d) is pyridyl,pyrimidinyl, or benzyl.

[0274] Representative compounds of the present invention, which areencompassed by Formula I, include, but are not limited to the compoundsin FIG. I and their pharmaceutically acceptable salts. Non-toxicpharmaceutically acceptable salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

[0275] The preset invention also encompasses the acylated prodrugs ofthe compounds of Formula I. Those skilled in the art will recognizevarious synthetic methodologies which may be employed to preparenon-toxic pharmaceutically acceptable addition salts and acylatedprodrugs of the compounds encompassed by Formula I.

[0276] By “aryl” and “Ar” is meant an aromatic carbocyclic group havinga single ring (e.g., phenyl), multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), whichcan optionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

[0277] By “alkyl” and “lower alkyl” is meant straight and branched chainalkyl groups having from 1-6 carbon atoms.

[0278] By “lower alkoxy” and “alkoxy” is meant straight and branchedchain alkoxy groups having from 1-6 carbon atoms.

[0279] By “hydroxy lower alkyl” or “hydroxy alkyl” is meant an alkylgroup substituted by at least one hydroxy group. Preferred hydroxy alkylgroups are straight chain alkyl groups substituted with one hydroxygroup at the terminal carbon atom.

[0280] By “heteroaryl” is meant 5, 6, or 7 membered aromatic ringsystems having at least one hetero atom selected from the groupconsisting of nitrogen, oxygen and sulfur. Examples of heteroaryl groupsare pyridyl, pyrimidinyl, pyrrolo, pyrazolo, pyrazinyl, pyridazinyl,oxazolo, furanyl, quinoline, isoquinoline, thiazole, and thienyl, whichcan optionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, hetroaryl, and hydroxy.

[0281] By “halogen” is meant fluorine, chlorine, bromine and iodine.

[0282] By “arylalkyl” is meant the group —R—Ar where Ar is an aryl groupand R is a straight or branched chain aliphatic group. Arylalkyl groupsmay optionally be substituted with, e.g., halogen, lower alkyl, loweralkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, and hydroxy.Preferred arylalkyl groups in the above formulas where W is CH and R₈represents arylalkyl are phenylalkyl groups where the alkyl portion islower alkyl. A particularly preferred phenylalkyl group is benzyl wherethe phenyl ring may be substituted with up to three substituentsindependently selected from hydrogen, halogen, trifluoromethyl, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms.

[0283] By “cycloalkyl” is meant cyclic hydrocarbons having from 3-8carbon atoms. These cyclic hydrocarbon groups may be substituted with upto three substituents independently selected from hydrogen, halogen,trifluoromethyl, cyano, straight or branched chain lower alkyl having1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6carbon atoms, or SO₂R₉ where R₉ is NH₂ or NHCH₃.

[0284] The pharmaceutical utility of compounds of this invention areindicated by the following assays for dopamine receptor subtypeaffinity.

[0285] Assay for D2 and D3 Receptor Binding Activity

[0286] Striatial tissue is dissected from adult male Sprague Dawley ratsor BHK 293 cells are harvested containing recombinantly produced D2 orD3 receptors. The sample is homogenized in 100 volumes (w/vol) of 0.05 MTris HCl buffer at 4° C. and pH 7.4. The sample is then centrifuged at30,000×g and resuspended and rehomogenized. The sample is thencentrifuged as described and the final tissue sample is frozen untiluse. The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffercontaining 100 mM NaCl.

[0287] Incubations are carried out at 48° C. and contain 0.5 ml oftissue sample, 0.5 nM ³H-raclopride and the compound of interest in atotal incubation volume of 1.0 ml. Nonspecific binding is defined asthat binding found in the presence of 10⁻⁴ M dopamine; without furtheradditions, nonspecific binding is less than 20% of total binding. Thebinding characteristics of examples of this patient are shown in Table 1for rat striatal homogenates. TABLE 1 Compound Number¹ IC₅₀ (mM) 1 0.9008 0.011 16 0.014 19 0.100 21 0.018 24 0.620 26 0.200

[0288] Assay for D4 Receptor Binding Activity

[0289] Clonal cell lines expressing the human dopamine D4 receptorsubtype were harvested in PBS and the cells centrifuged and the pelletsstored at −80° C. until used in the binding assay. The pellets wereresuspended and the cells lysed at 4° C. in 50 mM Tris pH 7.4 buffercontaining 120 mM NaCl, 1 mM EDTA and 5 mM MgCl₂. The homogenate iscentrifuged at 48000×g for 10 minutes at 4° C. The resulting pellet isresuspended in fresh buffer and centrifuged again. After resuspension ofthe pellet in fresh buffer at 100 ml aliquot is removed for proteindetermination. The remaining homogenate is centrifuged as above, thesupernatant removed and the pellet stored at 4° C. until needed at whichtime it is resuspended to a final concentration of 625 mg/ml (250 mg persample) with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior touse. Incubations were carried out for 60 minutes at 25° C. in thepresence of 0.1 nM [³H] YM-09151-2. The incubation was terminated byrapid filtration through Whatman GF/C filters and rinsed with 2×4 mlwashes of chilled 50 mM Tris (pH 7.4) and 120 mM NaCl. Non-specificbinding was determined with 1 mM spiperone and radioactivity determinedby counting in an LKB beta counter. Binding parameters were determinedby non-linear least squares regression analysis, from which theinhibition constant (ki) could be calculated for each test compound. Thebinding characteristics of some examples of this patent are shown inTable 2 for the dopamine D4 binding assay. In general, compounds of theaccompanying examples were tested in the above assay, and all were foundto possess a Ki value for the displacement of [³H]YM-09151-2 from thehuman dopamine D4 receptor subtype of below 500 nM. Some specific datain indicated in Table 2. TABLE 2 Compound Number¹ Ki (mM) 19 0.001 200.014 22 0.048 23 0.003 24 0.001 25 0.002 43 0.014 45 0.005 47 0.053 500.005 52 0.002 55 0.500 56 0.450 58 0.003 60 0.015 61 0.013 65 0.013

[0290] Compounds 8, 16, 19, 21, 23, 24, 25 and 52 are particularlypreferred embodiments of the present invention because of their potencyin binding to dopamine receptor subtypes.

[0291] The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

[0292] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

[0293] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0294] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0295] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide palatableoral preparations. These compositions may be preserved by the additionof an anti-oxidant such as ascorbic acid.

[0296] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0297] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil,for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

[0298] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitor or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also besterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0299] The compounds of general formula I may also be administered inthe form of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

[0300] Compounds of general formula I may be administered parenterallyin a sterile medium. The drug, depending on the vehicle andconcentration used, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

[0301] Dosage levels of the order of from about 0.1 mg to about 140 mgper kilogram of body weight per day are useful in the treatment of theabove indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

[0302] It will be understood, however, that the specific dose level forany particular patient will depend upon a variety of factors includingthe activity of the specific compound employed, the age, body weightgeneral health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

[0303] An illustration of the preparation of representative2-phenyl-4-aminomethyl-imidazoles of the present invention is shown inScheme I. Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present invention.

[0304] where

[0305] S₁, S₂, S₃, S₄, and S₅ are the same or different and representhydrogen, halogen, trifluoromethyl, cyano, straight or branched chainlower alkyl having 1-6 carbon atoms, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, straight or branched chain loweralkoxy having 1-6 carbon atoms, or SO₂R₉ where R₉ is NH2 or NHCH₃;

[0306] R5 and R6 are as defined as above for Formula I; or

[0307] NR₅R₆ together represent cyclic groups as defined above forFormula I.

[0308] Alternatively, compounds of the invention may be preparedaccording to the reactions shown in Scheme 2.

[0309] where

[0310] R₁, T, M, X, Y, Z, R₄, and R₅ are as defined for Formula V above.

[0311] The invention is illustrated further by the following exampleswhich are not to be construed as limiting the invention in scope orspirit to the specific procedures and compounds described in them.

EXAMPLE I

[0312]

[0313] A mixture of 6.45 g 5-bromo-o-anisaldehyde, 2.2 g ofhydroxylamine hydrochloride, 4.1 g of sodium formate and 20 mL formicacid were heated at 100° C. with stirring for 1 h. The reaction mixturewas poured onto ice water and the mixture was made basic by the carefuladdition of 50% sodium hydroxide. The product was extracted with ether,the ether extracts were dried over magnesium sulfate and the solvent wasremoved in vacuo. The residue was crystallized from ether/hexane toafford 5-bromo-2-methoxybenzonitrile.

EXAMPLE II

[0314]

[0315] A mixture of 4.0 g 5-bromo-2methoxybenzonitrile, 5 g 3A molecularsieves and 60 mL of anhydrous methanol was saturated with HCl gas at 0°C. and allowed to stand at 0° C. for 24 h. The solvent was removed invacuo and the residue taken up in 75 mL of anhydrous methanol andsaturated with ammonia gas at room temperature. The reaction mixture wasthen heated at 80° C. for 4 h in a sealed tube. The sovent was removedin vacuo, the reaction mixture was diluted with 3N HCl and washed withethyl acetate to remove unreacted nitrile. The aqueous layer was madebasic with 50% NaOH and the product was extracted three times with 10%methanol in methylene chloride. The combined organic extracts were driedover potassium carbonate and the solvents removed in vacuo to afford5-bromo-2-methoxybenzamidine as a glassy solid.

EXAMPLE III

[0316]

[0317] To a solution of 20 g 1,1,1,3,3,3-hexamethyldisilazane in 150 mLdry ether was added 5 mL 2.4 M n-butyllithium in hexane. After 10 min atroom temperature, 16.3 g 2,3-dimethoxybenzonitrile was added in oneportion and the mixture was kept at room temperature for 16 h. Thereaction mixture was then poured onto excess 3N HCl. The aqueous layerwas separated, basified with 50% NaOH and the product was extractedthree times with 10% methanol in methylene chloride. The combinedorganic extracts were dried over potassium carbonate and the solventsremoved in vacuo to afford 2,3-dimethoxybenzamidine as a glassy solid.

EXAMPLE IV

[0318]

[0319] A mixture of 1.5 g of 5-bromo-2-methoxybenzamidine, 1.0 g of1,3-dihydroxyacetone dimer, 1.3 g of ammonium chloride, 3 mL oftetrahydrofuran and 10 mL concentrated aqueous ammonium hydroxide washeated at 90° C. for 3 h. The reaction mixture was chilled on ice andthe precipitated product was collected and recrystallized from methanolto afford 2-(5-bromo-2-methoxyphenyl)-4-hydroxymethylimidazole as ayellow solid.

EXAMPLE V

[0320]

[0321] A mixture of 500 mg2-(5-bromo-2-methoxyphenyl)-4-hydroxymethylimidazole and 1.5 mL thionylchloride was heated at 80° C. for 15 min and then concentrated underreduced pressure. Diethyl ether (15 mL) was added and the resultingsolid was collected and washed with ether. This solid was added in oneportion to a mixture of 3 mL of dimethylamine, 15 mL isopropanol and 30mL of methylene chloride and the mixture was stirred for 20 min. Thesolvents were removed in vacuo and the residue was dissolved in 2N HCland washed two times with ethyl acetate. The aqueous layer was madebasic with 50% NaOH and the product was extracted with methylenechloride. The organic extracts were dried over magnesium sulfate, thesolvents removed in vacuo, and the residue was treated with ethanolicHCl/ether to afford2-(5-bromo-2-methoxyphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 1), m.p. 242-243° C.

EXAMPLE VI

[0322] The following compounds were prepared essentially according tothe procedure described in Examples I-V:

[0323] (a) 2-Phenyl-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 2), m.p. 259-260° C.

[0324] (b) 2-Phenyl-4(5)-(piperidinomethyl)-imidazole dihydrochloride(Compound 3), m.p. 245-247° C.

[0325] (c) 2-Phenyl-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 4), m.p. 239-240° C.

[0326] (d)2-(2-Methoxyphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 5), melting at X° C.

[0327] (e)2-(3-Methoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 6), m.p. 115-117° C.

[0328] (f)2-(2,3-Dimethoxyphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 7), m.p. 220-221° C.

[0329] (g)2-(2,3-Dimethoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 8), m.p. 200-202° C.

[0330] (h)2-(3-Methoxyphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 9), m.p. 213-214° C.

[0331] (i) 2-(3-Fluorophenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 10), m.p. 211-214° C.

[0332] (j)2-(2-Fluorophenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 11), m.p. 241-244° C.

[0333] (k) 2-(3-Methylphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 12), m.p. 231-234° C.

[0334] (l) 2-(2-Fluorophenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 13), m.p. 246-247° C.

[0335] (m)2-(4-Fluorophenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 14), m.p. 237-239° C.

[0336] (n)2-(2-Methoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 15), m.p. 239-241° C.

[0337] (o)2-(5-Bromo-2,3-dimethoxyphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 16), m.p. 194-194° C.

[0338] (p)2-(5-Bromo-2-methoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 17), m.p. 242-243° C.

[0339] (q)2-(5-Bromo-2,3dimethoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 18).

EXAMPLE VII

[0340]

[0341] A mixture of 350 mg 2-phenyl-4-hydroxymethylimidazole and 3 mLthionyl chloride was heated at 80° C. for 15 min. The excess thionylchloride was removed in vacuo and the residue was dissolved in 20 mL ofmethylene chloride. This solution was added to a mixture of 1 mLtriethylamine and 410 mg 1-(2-methoxyphenyl)piperazine in 20 mLmethylene chloride and the mixture was stirred for 20 min. The solventswere removed in vacuo and the residue was dissolved in 2N HCl and washedtwo times with ethyl acetate. The aqueous layer was made basic with 50%NaOH and the product was extracted with methylene chloride. The organicextracts were dried over magnesium sulfate, the solvents removed invacuo, and the residue was crystallized from ethyl acetate to afford2-phenyl-4(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]imidazole(Compound 19), m.p. 105-107° C.

EXAMPLE VIII

[0342] The following compounds were prepared essentially according tothe procedure described in Example VII:

[0343] (a)2-(4-Fluorophenyl)-4(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]-imidazole(Compound 20), m.p. 95-97° C.

[0344] (b)2-(2,3-Dimethoxyphenyl)-4(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 21), m.p. 217-218° C.

[0345] (c)2-(3-Chlorophenyl)-4(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 22), m.p. 198-199° C.

[0346] (d)2-Phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)methyl]-imidazoledihydrochloride (compound 23), m.p. 246-248° C.

[0347] (d′)2-Phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledimaleate (compound 23A), m.p. 176-178° C.

[0348] (e)2-Phenyl-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 24), m.p. 176-177° C.

[0349] (f) 2-Phenyl-4(5)-[(4-benzyl-piperidin-1-yl)methyl]-imidazoledihydrochloride (Compound 25), m.p. 234-236° C.

[0350] (g) 2-Phenyl-4(5)-[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 26), m.p. 238-240° C.

[0351] (h)2-Phenyl-4(5)-[(1,2,3,4-tetrahydroisoquinolin)-2-yl-methyl]-imidazoledihydrochloride (Compound 27).

[0352] (i) 2-Phenyl-4(5)-2-phenyl-5,6,7,8,-tetrahydrobenzimidazoleimidazole dihydrochloride (Compound 76).

EXAMPLE IX

[0353] The following compounds were prepared essentially according tothe procedures described in Examples I-VII:

[0354] (a)2-(2,3-Dimethoxyphenyl)-4(5)-[(1,2,3,4-tetrahydroisoquinolin)-2-yl-methyl]-imidazoledihydrochloride (Compound 28), m.p. 205-207° C.

[0355] (b)2-(4-Methoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 29).

[0356] (c)2-(3,4-Dimethoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 30).

[0357] (d) 2-(3-Methoxyphenyl)-4(5)-[(N-methyl)aminomethyl]-imidazoledihydrochloride (Compound 31).

[0358] (e)2-(5-Chloro-2-methoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole(Compound 32), m.p. 88-89° C.

[0359] (f)2-(5-Chloro-2-methoxyphenyl)-4(5)-[(N,N-dimethyl)aminomethyl]-imidazoledihydrochloride (Compound 33), m.p. 231-233° C.

[0360] (g)2-(5-Chloro-2-methoxyphenyl)-4(5)-[(N-methyl)aminomethyl]-imidazoledihydrochloride (Compound 34), m.p. 225-227° C.

[0361] (h)2-(5-Chloro-2-methoxyphenyl)-4(5)-[(N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 35), m.p. 184-186° C.

[0362] (i)2-(5-Chloro-2-benzyloxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 36), m.p. 118-123° C.

[0363] (j)2-(2-Benzyloxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 37), m.p. 199-200° C.

[0364] (l)2-(3-Ethylphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 38), m.p. 234-235° C.

[0365] (m)2-(5-Chloro-2-methoxyphenyl)-4(5)-[(N-methyl-N-(-4-chlorobenzyl))aminomethyl]-imidazoledihydrochloride (Compound 39), m.p. 186-188° C.

[0366] (n)2-(5-Chloro-2-hydroxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 40), m.p. 227-228° C.

[0367] (o)2-(5-Bromo-2-benzyloxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 41).

[0368] (p)2-(5-Ethyl-2-methoxyphenyl)-4(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 42), m.p. 114-115° C.

[0369] (q)2-(5-Chloro-2-methoxyphenyl)-4(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 43), m.p. 138-143° C.

[0370] (r)2-(5-Chloro-2-methoxyphenyl)-4(5)-[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 44), m.p. 138-143° C.

[0371] (s) 2-Phenyl-4(5)-[(4-phenyl-piperazin-1-yl)methyl]-imidazole(Compound 45), m.p. 189-191° C.

[0372] (t)2-(4-Fluorophenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl)-imidazoledihydrochloride (Compound 46), m.p. 260-264° C. (dec).

[0373] (u)2-(4-Methoxyphenyl)-4(5)-[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 47), m.p.196-199° C.

[0374] (v)2-Phenyl-4(5)-[(4-(3-trifluoromethylphenyl)-piperazin-1-yl-)methyl]imidazole(Compound 48), m.p.182-184° C.

[0375] (w)2-(2-Methoxyphenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 49).

[0376] (x)2-(3-Methoxyphenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 50), m.p.114-117° C.

[0377] (y)2-(3-Fluorophenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazole(Compound 51), m.p. 110-112° C.

[0378] (z)2-(2-Fluorophenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledimaleate (Compound 52), m.p. 142-144° C.

[0379] (aa)2-(2-Methylphenyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 53), m.p.242-244° C.

[0380] (ab)2-(5-Ethyl-2-methoxyphenyl-4(5)-[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 54), m.p.76-78° C.

[0381] (ac)2-(5-Ethyl-2-methoxyphenyl-4(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 55), m.p.61-64° C.

[0382] (ad)2-Phenyl-4(5)-[(4(4-fluorophenyl)-piperazin-1yl-)methyl]imidazoledihydrochloride (Compound 56), m.p.64-68° C.

[0383] (ae)2-(5-Ethyl-2-methoxyphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 57), m.p.75-78° C.

[0384] (af)2-Phenyl-4(5)-[(4(4-fluoro-2-pyrimidinyl)-piperazin-1yl)-methyl]imidazoledihydrochloride (Compound 58), m.p.188-190° C.

[0385] (ag)2-(4-Fluorophenyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 59), m.p.181-184° C.

[0386] (ah)2-Phenyl-4(5)-[(4(5-chloro-2-methylphenyl)-piperazin-1yl-)-methyl]imidazoledihydrochloride (Compound 60), m.p.142-145° C.

[0387] (ai)2-Phenyl-4(5)-[(4(3,4-dichlorophenyl)-piperazin-1yl-)methyl]imidazole(Compound 61), m.p.179-181° C.

[0388] (aj)2-Phenyl-4(5)-[(4(4-fluorophenyl)-piperidin-1yl-)methyl]imidazoledimaleate (Compound 62), m.p.148-149° C.

[0389] (ak)2-(3-Fluorophenyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazoledimaleate (Compound 63), m.p.148-149° C.

[0390] (al)2-(4-Fluorophenyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 64), m.p. 254-256° C.

[0391] (am)2-Phenyl-4(5)-[(4-(4-fluorobenzyl)-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 65).

[0392] (an)2-(2-Fluorophenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 66), m.p. 159-161° C.

[0393] (ao)2-(4-Methylphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 67), m.p.176-179° C.

[0394] (ap)2-(2-Fluorophenyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazoledimaleate (Compound 68), m.p.113-115° C.

[0395] (aq)2-(4-Chlorophenyl-4(5)-[(4(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole(Compound 69), m.p. 176-177° C.

[0396] (ar)2-Phenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledimaleate (Compound 70), m.p.185-186° C.

[0397] (as)2-(2-Fluorophenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledimaleate (Compound 71), m.p.172-173° C.

[0398] (at)2-(4-Fluorophenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledimaleate (Compound 72), m.p.183-184° C.

EXAMPLE X

[0399]

[0400] A solution of 40 mL tetrahydrofuran containing 1.0 g of2-phenylimidazole was cooled to 0° C. and 4 mL of 2M lithiumdiisopropylamide was added dropwise which resulted in the formation of awhite suspension. The mixture was stirred for 10 min at 0° C. and then0.7 mL of dimethyl sulfate was added. The reaction was allowed to stirat room temperature for an additional 30 min during which tie thesolution became homogeneous. Aqueous ammonium chloride was added and thetetrahydrofuran was removed by evaporation under reduced pressure. Theaqueous phase was extracted with 2×100 mL aliquots of dichloromethane.The combined organic extracts were washed with dilute ammonium hydroxideand brine. The combined organic extracts were dried over anhydroussodium sulfate and concentrated under reduced pressure to yield 1 g of1-methyl-2-phenylimidazole which was used in the next step withoutfurther purification or characterization.

[0401] To a solution of 1 g of 1 methyl-2-phenylimidazole in 10 mLacetic acid were added 0.4 mL of 37% aqueous formaldehyde and 1.2 mL of4-benzylpiperidine. The reaction mixture was heated at 100° C. for 10hours and the acetic acid then removed by evaporated under reducedpressure. The residue was dissolved in water and made alkaline with 5%sodium hydroxide and extracted with 2×100 mL of dichloromethane. Thecombined extracts were dried over anhydrous sodium sulfate andconcentrated to small volume under reduced pressure to give 1methyl-2-phenyl-4-[(4-benzylpiperidin-1-yl)methyl]-imidazole.

[0402] The following compounds were prepared essentially according tothe procedure described in Example X utilizing2-phenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methylimidazole(Compound 22) as starting material. The resulting isomers were separatedby chromatography on silica gel using ethyl acetate as eluant.

[0403] a)1-Methyl-2-phenyl-4-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazole(Compound 74).

[0404] b)1-Methyl-2-phenyl-5-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazole(Compound 75).

EXAMPLE XI

[0405]

[0406] A mixture of 3 g of ethylthiooxamate, 4.25 g of2-aminoacetophenone hydrochloride and 3.69 g of sodium acetate wasdissolved in 20 mL of acetic acid and heated under reflux for 3 hr. Thereaction mixture was allowed to cool to room temperature and the aceticacid removed by evaporation under reduced pressure. The residue wasbasified with aqueous sodium carbonate and extracted with 2×100 mL ofethyl acetate. The combined extracts were washed with 2×100 mL of brine,dried over anhydrous sodium sulfate and the solvent removed underreduced pressure to yield 2.8 g of ethyl 4-phenylimidazole-2-carboxylateas a solid which was used in the next step without further purificationor characterization.

[0407] To a solution of 2.75 g ethyl-4-phenylimidazole-2-carboxylate in20 mL tetrahydrofuran was added a suspension of 0.5 g lithium aluminumhydride in 30 mL of tetrahydrofuran. The reaction mixture was stirred atroom temperature overnight, poured into 100 mL of ice water andextracted with 2×100 mL of ethyl acetate. The combined extracts werewashed with 2×100 mL of brine, dried over anhydrous sodium sulfate andthe solvent removed under reduced pressure to yield 2 g of2-hydroxymethyl-4-phenylimidazole which was used in the next stepwithout further purification or characterization.

[0408] A solution of 1 g of 2-hydroxymethyl-4-phenylimidazole in 10 mLof thionyl chloride was heated at 60° C. for 1 hr. After removal ofexcess thionyl chloride by evaporation under reduced pressure, theresidue was treated with a solution of 1 g 4-benzylpiperidine and 2 gN,N,-diisopropylethylamine in 50 mL of chloroform. The reaction mixturewas stirred at 60° C. for 1 hr, allowed to cool to room temperature andwashed successively with 50 mL of 1N sodium hydroxide solution and 50 mLof water. The organic phase was then dried over anhydrous sodium sulfateand the solvent evaporated under reduced pressure to yield 850 mg of4phenyl-2(5)-[(4-benzylpiperidin-1-yl)-methyl]imidazole which wasconverted into its monofumarate salt (Compound 77), mp 155-157° C.

EXAMPLE XII

[0409] The following compounds were prepared essentially according tothe procedure described in Example XI.

[0410] (a) 4-Phenyl-2(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazoledihydrochloride (Compound 78), m.p. 229-231° C.

[0411] (b)4-Phenyl-2(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 79), m.p.178-180° C.

[0412] (c)4-Phenyl-2(5)-[4-(4-fluoro-benzyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 80), m.p. 216-218° C.

[0413] (d) 4-Phenyl-2(5)-[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 81), m.p.182-184° C.

[0414] (e)4-Phenyl-2(5)-[(4(4-fluorophenyl)-piperazin-1yl-)methyl]imidazoledihydrochloride (Compound 82), m.p.161-163° C.

[0415] (f)4-Phenyl)-2(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride (Compound 83), m.p. 229-231° C.

[0416] (g)4-Phenyl-2(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazoletrihydrochloride (Compound 84), m.p. 165-167° C.

[0417] (h) 4-Phenyl-2(5)-[(4-phenyl-piperazin-1yl-)methyl]imidazoledihydrochloride (Compound 85), m.p. 182-184° C.

[0418] (i) 4-Phenyl-2(5)-[(4-benzoyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 86) m.p. 200-202° C.

[0419] (j)4-Phenyl-2(5)-[(4-(4-fluoro-benzoyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride (Compound 87), m.p.173-175° C.

EXAMPLE XIII

[0420]

[0421] A solution of 10 g of 2-bromopropiophenone in 50 mL formamide washeated at 180° C. overnight. The reaction was then allowed to cool toroom temperature and poured into 250 mL ice water. The mixture wasadjusted to pH 9 with 1N sodium hydroxide and the resulting precipitatewas collected by filtration, washed with water and dried to yield 6.0 gof 4-methyl-5-phenylimidazole as a solid which was used in the next stepwithout further purification.

[0422] A mixture of 128 mg 4-methyl-5-phenylimidazole, 180 mg of4-benzylpiperidine and 85 mg of 37% formaldehyde in 10 mL acetic acidwas heated under reflux for 8 hr. The acetic acid was then removed byevaporation under reduced pressure and the residue was dissolved in 50mL ethyl acetate. The ethyl acetate solution was washed successivelywith 50 mL of dilute sodium hydroxide solution and water. The ethylacetate extract was then dried over anhydrous sodium sulfate and thesolvent removed by evaporation under reduced pressure to yield5-methyl-4-phenyl-2(5)-[(4-benzyl-piperidin-1-yl)-methyl]imidazole as anoil which was purified by chromatography on silica gel using 5% methanolin methylene chloride as eluent. Treatment of the purified free basewith ethanolic HCl yielded5-methyl-4-phenyl-2(5)-[(4-benzyl-piperidin-1-yl)-methyl]imidazoledihydrochloride (Compound 88).

EXAMPLE XIV

[0423]

[0424] To a solution of 14.3 g 2-phenyl-4(5)-methylimidazole and 13.8 gof 1-(2-pyrimidyl)piperazine in 50 mL of ethanol was added a solution of7.1 mL of aqueous formaldehyde. The resulting mixture was heated atreflux temperature for 2 hr and allowed to cool to room temperature. Thesolid was collected by filtration and dried to yield 20 g of2-phenyl-5-methyl-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]imidazolewhich was treated with 2 equivalents of maleic acid in isopropanol toyield2-phenyl-5-methyl-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazoledimaleate (Compound 89), m.p. 172-174° C.

EXAMPLE XV

[0425]

[0426] To a solution of 100 mg of2-phenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]imidazole in 10mL of chloroform was added one equivalent (80 mg) of iodine in 5 mL ofchloroform followed by 0.5 mL of triethylamine. The reaction mixture wasstirred at room temperature for 30 min during which time a solidcrystallized from the solution. The solid was collected by filtration toyield 52 mg of2-phenyl-5-iodo-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazolehydroiodide salt (Compound 90) which had a m.p. of 196-199° C.

EXAMPLE XVI

[0427]

[0428] To a solution of 220 mg of 2-phenyl-4-imidazole carboxaldehyde in5 mL of tetrahydrofuran was added 6.4 mL of a 1 L methyllithium solutionin tetrahydrofuran. The reaction mixture was quenched with 50 mL ofwater and the mixture extracted with 2×50 mL aliquots of ethyl acetate.The combined ethyl acetate extracts were dried over anhydrous sodiumsulfate, filtered and the solvent evaporated under reduced pressure toyield 250 mg of 2-phenyl-4(5)-(1-hydroxyethyl)imidazole which was usedin the next step without further purification or characterization. Theresidue of 2-phenyl-4(5)-(1-hydroxyethyl)imidazole was dissolved in 8 mLof thionyl chloride and heated at reflux temperature for 30 min afterwhich the thionyl chloride was removed by distillation under reducedpressure to yield 250 mg of 2-phenyl-4(5)-(1-chloroethyl)imidazole as anoil which was used in the next step without additional purification orcharacterisation. This oil was dissolved in 10 mL of chloroform and tothis solution was added 224 mg of 4-benzylpiperidine and 2 mL oftriethylamine. The reaction was allowed to stand at room temperature for10 min and then washed with 50 mL 1N sodium hydroxide. The chloroformextract was then separated and dried over anhydrous sodium sulfate,filtered and the solvent removed by evaporation under reduced pressureto yield 2-phenyl-4(5)-[(1-((4-benzyl-piperidin-1-yl)-ethyl)}imidazolewhich was purified by chromatography on silica gel using 10%methanol/dichloromethane as eluent. Treatment with ethanolic HCl yielded2-phenyl-4(5)-[1-((4-benzyl-piperidin-1-yl)-ethan-1-yl)]imidazoledihydrochloride salt (Compound 91), m.p. 169-171° C.

EXAMPLE XVII

[0429]

[0430] A solution of 5.5 g 1-cyanonaphthalene in 150 mL dry ether wascooled to 0° C. To this solution 12.1 g lithium bis(trimethylsilyl)amidewas added in one portion. The mixture was stirred for 12 hours andallowed to warm to room temperature. The reaction mixture was cooled to0° C. then quenched by the addition of 200 mL 3N HCl. After stirring 20minutes at 0° C., the mixture was transferred to a separatory funnel andwashed 3×100 mL ether. The aqueous layer was cooled on an ice bath andadjusted to pH 14 with solid sodium hydroxide. This solution wasextracted 4×100 mL dichloromethane. The combined organic extracts werewashed 2×100 mL water, 1×100 mL brine, dried over potassium carbonate,filtered, then concentrated under reduced pressure to give 3.6 g of thedesired amidine which was used without further purification.

[0431] A mixture of 3.6 g of the crude amidine, 2.5 g ofdihydroxyacetone dimer, and 2.5 g of ammonium chloride were suspended in35 mL conc. ammonium hydroxide in a pressure tube. The mixture washeated to 90° C. for 3 hours during which time the amidine dissolved andthe product precipitated out. The reaction mixture was cooled to roomtemperature and the product collected by filtration, washed with coldwater, and dried in vacuo to give 3 g2-(1-naphthyl)-4(5)-(hydroxymethyl)imidazole as off-white crystals, m.p.155-158° C.

[0432] A solution of 62 mg 2-(1-naphthyl)-4(5)-(hydroxymethyl)imidazolewas dissolved in 3 mL of thionyl chloride and warmed to 60° C. for 2hours. The solvent was removed and the residue was dissolved in 3 mLchloroform and 53 mg 4-benzylpiperidine was added followed by 47 mg ofdiisopropylethylamine. The reaction mixture was stirred at roomtemperature for 1 hour, diluted with 3 volumes of chloroform, thenwashed 3×3 mL of 10% sodium hydroxide. The organic layer was dried overanhydrous sodium sulfate, filtered, then concentrated under reducedpressure. The residue was purified by chromatography on silica geleluting with 5% methanol in dichloromethane to yield 62 mg of2-(1-naphthyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]imidazole(Compound 92), m.p. 81-83° C.

EXAMPLE XVIII

[0433] The following compounds were prepared from the correspondingnitriles essentially according to the procedures described in ExampleXVII.

[0434] (a)2-(1-Naphthyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 93), m.p.187-188° C.

[0435] (b)2-(1-Naphthyl)-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole(Compound 94), m.p. 182-183° C.

[0436] (c) 2-(1-Naphthyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole(Compound 95), m.p. 74-76° C.

[0437] (d)2-(2-Naphthyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole(Compound 96), m.p. 92-94° C.

[0438] (e)2-(2-Naphthyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 97), m.p.218-219° C.

[0439] (f)2-(2-Naphthyl)-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole(Compound 98), m.p. 199-201° C.

[0440] (g) 2-(2-Naphthyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole(Compound99), m.p. 86-87° C.

[0441] (h)2-(2-Pyridyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole(Compound 100), m.p. 96-98° C.

[0442] (i)2-(2-Pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 101), m.p. 134-135° C.

[0443] (j)2-(2-Pyridyl)-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole(Compound 102), m.p. 135-137° C.

[0444] (k) 2-(2-Pyridyl)-4 (5)-[(N-methyl-N-benzyl)-methyl]-imidazole(Compound 103), m.p. 61-63° C.

[0445] (l)2-(3-Pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 104), m.p. 155-157° C.

[0446] (m) 2-(3-Pyridyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole(Compound 105), m.p. 141-142° C.

[0447] (n)2-(4-Pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 106), m.p. 154-156° C.

[0448] (o)2-(2-Pyrazinyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole(Compound 107), m.p. 80-81° C.

[0449] (p)2-(2-Pyrazinyl)-4(5)-[(4-(2-pyrimidinyl)-piperizin-1-yl)-methyl]-imidazole(Compound 108), m.p. 164-165° C.

[0450] (q) 2-(2-Pyrazinyl)-4(5)-[((N-methyl-N-benzyl)-methyl]-imidazole(Compound 109), m.p. 93-94° C.

[0451] (r)2-(2-Thienyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole(Compound 110), m.p. 77-79° C.

[0452] (s)2-(2-Thienyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 111), m.p. 204-205° C.

[0453] (t) 2-(2-Thienyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole(Compound 112), m.p. 132-134° C.

[0454] (u)2-(2-Thienyl)-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole(Compound 113), m.p. 179-181° C.

[0455] (v)2-(2-Quinolinyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 114), m.p. 263° C. (dec).

[0456] (w) 2-(2-Quinolinyl)-4 (5)-[(N-methyl-N-benzyl)-methyl]-imidazole(Compound 115), m.p. 247° C. (dec).

EXAMPLE XIX

[0457]

[0458] A solution was prepared by dissolving 193 mg of2-benzoylimidazole, 330 mg of 1-(2-pyrimidyl)-piperazine and 165 mL of a37% solution of formaldehyde in 1 mL of acetic acid and the resultingmixture was heated to 100° C. for 15 hours. The mixture was then cooledto 0° C., basified with 3 N hydrochloric acid, then extracted with 5×10mL of ethyl acetate. The organic extracts were washed with 2×10 mLwater, 1×10 mL of brine, dried over anhydrous sodium sulfate, filtered,then concentrated under reduced pressure. The residue waschromatographed on silca gel using 5% methanol in dichloromethane aseluent to yield 43 mg of2-(benzoyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 116), m.p. 177-179° C.

EXAMPLE XX

[0459] The following compounds were prepared essentially according tothe procedures described in Example XVII.

[0460] a)2-Benzyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 117), m.p. 160-161° C.

[0461] (b)2-(5-Methoxy-3,4-dihydro-naphth-1-yl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole(Compound 118), m.p. 133-134° C.

EXAMPLE XXI

[0462]

[0463] A solution of 1.25 g of 2-phenyl-4(5)-imidazole propenoic acidwas dissolved in 20 mL thionyl chloride and heated at reflux temperaturefor 2 hours. The solvent was removed and the residue suspended in 20 mLchloroform. To this solution was added 1.7 g of1-(2-pyrimidinyl)-piperazine dihydrogen chloride followed by 3.5 mL ofdiisopropylethylamine. The reaction mixture was stirred for 6 hours atroom temperature then diluted with 50 mL chloroform, washed with 3×20 mLof 10% sodium hydroxide solution, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue waschromatographed on silica gel using 5% methanol in dichloromethane aseluent to yield 554 mg of2-phenyl-4(5)-[(4(2-pyrimidinyl)-piperazin-1-yl)-propen-1-oyl]-imidazole(Compound 119), m.p. 235-236° C.

EXAMPLE XXII

[0464] The following compounds were prepared according to the proceduredescribed in Example XXI:

[0465] (a)2-Phenyl-4(5)-[(4-phenyl-piperazin-1-yl)-propen-1-oyl]-imidazole(Compound120), m.p.151-152° C.

[0466] (b)2-Phenyl-4(5)-[(4-hydroxy-4-(4-chlorophenyl)-piperidin-1-yl)-propen-1-oyl]-imidazole(Compound121), m.p. 236-240° C.

EXAMPLE XXIII

[0467]

[0468] A solution of 68 mg2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-propen-1-oyl]-imidazolewas dissolved a mixture of in 2 mL ethyl acetate and 0.2 ml ethanol andthe suspension was stirred for 2 days under a H₂ atmosphere, using 20 mgPt on carbon as catalyst. The mixture was filtered through Celite andthe solvent removed. The residue was chromatographed on silca gel using5% methanol/dichloromethane as eluent to yield 37 mg2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-propan-1-oyl]-imidazole(Compound 122), m.p.143-148° C.

EXAMPLE XXIV

[0469] The following compounds were prepared according to the proceduredescribed in Example XXIII

[0470] (a)2-Phenyl-4(5)-[(4-phenyl-piperazin-1-yl)-propan-1-oyl]-imidazole(Compound 123), m.p. 180-183° C.

[0471] (b)2-Phenyl-4(5)-[(4-(2-(3,4,5,6-tetrahydro)-pyrimidinyl)-piperazin-1-yl)-propan-1-oyl]-imidazole(Compound 124), m.p. 210-211° C.

EXAMPLE XXV

[0472]

[0473] To a solution of 84 mg2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-propan-1-oyl]-imidazolein 5 mL dry tetrahydrofuran at room temperature was added 18 mg oflithium aluminum hydride and the mixture was heated at refluxtemperature refluxed for 2 hours. After quenching with ethyl acetate,the solvent was removed under reduced pressure. The residue waschromatographed on silca gel using 10% methanol in dichloromethane aseluent to yield 20 mg of2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-propan-1-yl]-imidazole(Compound 125), m.p.133-135° C.

EXAMPLE XXVI

[0474] The following compounds were prepared according to the proceduredescribed in Example XXV.

[0475] (a)2-Phenyl-4(5)-[(4-phenyl-piperazin-1-yl)-propan-1-yl]-imidazole(Compound 126), m.p. 50-54° C.

[0476] (b)2-Phenyl-4(5)-[(4-hydroxy-4-(4-chlorophenyl)-piperidin-1-yl)-propan-1-yl]-imidazole(Compound 127), m.p. 122-124° C.

EXAMPLE XXVII

[0477]

[0478] To a solution of 6.8 g of 2-phenylimidazole in 200 mL 3Nhydrochloric acid was added 5% Rhodium on Carbon, Degussa type G10 NB/W.The mixture was hydrogenated at 100 psi for 24 hours then filteredthrough celite. The solution was neutralized with 25% sodium hydroxideand extracted with 2×100 mL ethyl acetate. The combined extract waswashed with 200 mL of brine and dried over anhydrous sodium sulfate.Evaporation of the solvent gave 2-cyclohexylimidazole as a fluffy, whitesolid which was used in the next step without further purification orcharacterization.

[0479] To a solution of 251 mg 2-cyclohexylimidazole in 8 mL of aceticacid, 274 mg of 1-(2-pyrimidyl)piperazine and 88 microliters of 37%formaldehyde were added. The solution was heated at 100° C. for 12 hoursthen the solvent was removed under reduced pressure and the residue wasdiluted with water. The mixture was made slightly alkaline with 5%sodium hydroxide and then extracted with 2×25 mL of ethyl acetate. Thecombined extracts were washed with 25 mL of brine, dried over anhydroussodium sulfate and the solvent removed by evaporation under reducedpressure. The products were separated on reverse phase silica gel(Whatman PLKC18F) using 0.2 M aqueous sodium chloride with 80% methano.Evaporation of the individual fractions yielded2-cyclohexyl-4(5)-hydroxymethyl imidazole and 50 mg of the desired2-cyclohexyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 128), m.p.210-213° C.

EXAMPLE XXVIII

[0480] The following compounds were prepared essentially according tothe procedure described in Example XXVII.

[0481] (a)2-cyclohexyl-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole (Compound129), m.p. 185-188° C.

[0482] (b) 2-cyclohexyl-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole(Compound 130), m.p.235-238° C.

[0483] (c)2-(4-methylcyclohexyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 131).

EXAMPLE XXIX

[0484]

[0485] A solution of 790 mg of iodine in 5 mL of chloroform was added to1.0 g of2-phenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]imidazoledissolved in 30 mL of chloroform at ambient temperature. After thesolution was stirred for 10 minutes 1 mL of triethylamine was added andstirring was continued until no more solids formed. The solid wascollected by filtration and after drying yielded 700 mg of2-phenyl-5-iodo-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazolewhich was used in the next step without further purification orcharacterization.

[0486] To a solution of 53 mg2-phenyl-5-iodo-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazolein 1 mL of dimethylformamide was added 130 microliters ofphenyltrimethylstannane and 3 mg ofbis(triphenylphosphine)-palladium(II) chloride. The reaction mixture washeated at 100° C. for 4 hours then poured into water and extracted with2×10 mL of ethyl acetate and washed with 10 mL of 10% ammoniumhydroxide. The combined organic extracts were dried over anhydroussodium sulfate and the solvent removed by evaporation under reducedpressure. The resulting material was chromatographed on silica gel with5% methanol in dichloromethane as eluant to yield 15 mg of2,5-diphenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazole(Compound 132), m.p. 221-225° C.

EXAMPLE XXX

[0487]

[0488] To a solution of 12.4 g p-tolunitrile in 500 mL of diethyl etherwas added 23 g of solid lithium bis(trimethylsilyl)amide at ambienttemperature. The mixture was stirred for 2 hours then hydrolysed with10% HCl at 0° C. The mixture was stirred for an additional 30 minutesand then concentrated to dryness to yield 6 g of 4-methylbenzamidinehydrochloride which was used in the next step without furtherpurification.

[0489] A solution of 4 g 4-methylbenzamidine hydrochloride in 60 mLammonium hydroxide was treated with 4.0 g with dihydroxyacetone and 4.8g ammonium chloride. The reaction mixture was heated to 90° C. for 4hours in a sealed tube. On cooling to room temperature a the solidformed was collected by filtration to yield 3.0 g2-(4-methylphenyl)-5-hydroxymethyl-imidazole which was convertedaccording to the procedure described in Example VII to yield2-(4-methylphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 133), m.p.178-180° C.

EXAMPLE XXXI

[0490] The following compounds were prepared according to the proceduredescribed in Example XXX.

[0491] (a)2-(4-Iodophenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole(Compound 134), m.p.218-220° C.

[0492] (b)2-Phenyl-4(5)-[(4-(4-chlorophenyl)-3-methylpiperazin-1-yl)methyl]imidazole(Compound 135), m.p. 137-139° C.

[0493] (c)2-Phenyl-4(5)-[(4-(4-methylphenyl)-3-methylpiperazin-1-yl)methyl]imidazole(Compound 136), m.p. 172-174° C.

[0494] (d)2-Phenyl-4(5)-[(4-(4-methoxyphenyl)-3-methylpiperazin-1-yl)methyl]imidazole(Compound 135), m.p. 183-190° C.

EXAMPLE XXXII

[0495]

[0496] To a solution of 6.3 g benzamidine hydrochloride in 60 mLammonium hydroxide was added 4.6 g 2-hydroxycyclohexanone. The reactionmixture was heated to 90° C. for 7 hours in a sealed tube. On cooling toroom temperature the crystals formed were collected by filtration andafter drying yielded 3.0 g 2-phenyl-4,5,6,7,-tetrahydrobenzimidazole(Compound 136), m.p. 300-301° C.

[0497] To a solution of 50 mg 2-phenyl-5,6,7,8-tetrahydrobenzimidazolein 5 mL carbon tetrachloride was added 40 mg1,3-dibromo-5,5-dimethylhydantoin. The mixture was heated to reflux andirradiated with a 500 W Tungsten lamp for 30 min. The temperature waslowered momentarily and a solution of 41 mg 1-(2-pyrimidyl)piperazinewas added to the reaction. The mixture was again heated at refluxtemperature for 30 min. Then 0.5 mL triethylamine was added to thereaction and the solution was stirred for 1 hour at room temperature.The volatiles were evaporated under reduced pressure and the product waspurified on silica gel with 10% methanol in dichloromethane to yield 28mg2-phenyl-7-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-4,5,6,7-tetrahydrobenzimidazole(Compound 137), m.p. 200-202° C.

EXAMPLE XXXIII

[0498] The following compounds were prepared according to the proceduredescribed in Example XXXII.

[0499] (a)2-phenyl-7-[(4-benzyl-piperidin-1-yl)-methyl]-4,5,6,7-tetrahydrobenzimidazole(Compound 138), m.p. 189-191° C.

[0500] (b)2-phenyl-7-[(N-methyl-N-benzyl)aminomethyl]-4,5,6,7-tetrahydrobenzimidazole(Compound 139), m.p. 181-183° C.

EXAMPLE XXXIV

[0501]

[0502] A solution of 820 mg 2-chloropyrimidine and 1.6 gcis-2,6-dimethylpiperazine in 25 mL toluene was heated at refluxtemperature for 12 hours. The solvent was evaporated the residue wasbasified with 5% sodium hydroxide and extracted with 2×100 mL ofdichloromethane. The combined organic extracts were dried over anhydroussodium sulfate and concentrated to givecis-2,6-dimethyl-1-(2-pyrimidyl)-piperazine. This amine was then used toprepare2-phenyl-4(5)-[(4-(2-pyrimidinyl)-cis-2,6-dimethylpiperazin-1-yl)-methyl]-imidazole(Compound 140), m.p. 130-135° C., according to the procedures describedin Example VIII.

EXAMPLE XXXV

[0503] The following compounds were prepared according to the proceduredescribed in Example XXXIV.

[0504] (a)2-phenyl-4(5)-[(4-(2-pyrimidinyl)-trans-2,5-dimethylpiperazin-1-yl)-methyl]-imidazole(Compound 141), m.p.175-178° C.

[0505] (b)2-phenyl-4(5)-[(8-(2-pyrimidinyl)-3-8-diazabicyclo(3.2.1)octan-3-yl)-methyl]-imidazole(Compound 142), m.p. 190-194° C.

EXAMPLE XXXVI

[0506]

[0507] A mixture of 5.0 g 1,4-dihydroxy-2-butanone and 7.5 g benzamidinedihydrochloride in 70 mL ammonium hydroxide was heated to 90° C. for 5hours in a sealed tube. The reaction mixture was diluted with 100 mLwater, extracted with 2×50 mL chloroform, dried over anhydrous sodiumsodium sulfate and the solvent removed by evaporation under reducedpressure. The residue was chromatographed on silica gel using 10%methanol in dichloromethane as eluent to yield 1.0 g2-phenyl-4(5)-hydroxyethylimidazole which was reacted with1-(2-pyrimidyl)piperazine according to the procedure Example VIII toyield2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-ethan-1-yl]-imidazole(Compound 143), m.p. 142-144° C.

EXAMPLE XXXVII

[0508]

[0509] A mixture of 77 mg 2-phenylimidazole-4(5)-carboxylic acid and 5mL of thionyl chloride was heated at reflux temperature for 1 hr. Thethionyl chloride was removed under reduced pressure to yield 75 mg of2-phenylimidazole-4-carboxylic acid chloride which was then dissolved in5 mL chloroform and treated with 67 mg 1-(2-pyrimidyl)piperazine. Thesolution was heated at reflux temperature for 1 hr and then 0.5 mLtriethylamine was added. The solution was stirred for another hour,concentrated under reduced pressure and the residue chromatographed onsilica gel using 10% methanol in dichloromethane as eluent to yield 50mg2-phenyl-4(5)-N-[(4-(2-pyrimidinyl)-piperazin-1-yl)-carboxamido]-imidazole(Compound 144), m.p. 231-232° C.

EXAMPLE XXXVIII

[0510] The following compounds were prepared according to the proceduredescribed in Example XXXVII.

[0511] (a) 2-phenyl-4(5)-N-[(N-methyl-N-benzyl)-carboxamido]-imidazole(Compound 145), characterized as oxalate salt m.p. 198-199° C.

[0512] (b)2-phenyl-4(5)-N-[(4-benzyl-piperidin-1-yl)-carboxamido]-imidazole(Compound 146), characterized as the hydrochloride salt, m.p. 179-181°C.

EXAMPLE XXXIX

[0513] The following compounds were assayed for D2, D3, and D4 receptorbinding activity using the assays described above. Receptor BindingActivity (Ki, nM) Dopamine Receptor Compound No. D2 D3 D4 45 239 169 523 1033 8200 2.7 24 1029 123 0.85

EXAMPLE XXXX

[0514] Summary

[0515] The effects of2-phenyl-4(5)-[(4-(2-pyrimidyl)-piperazin-1-yl)methyl]-imidazoledihydrochloride (Compound 23) and clozapine were evaluated in thefollowing models of learning and memory: a step-down passive avoidancetask assay and a modified Morris water maze assay. Separate groups ofmale Sprague Dawley rats were pretreated with either Compound 23 orclozapine prior to training in these tasks. The control compound,clozapine, produced an acquisition deficit in the passive avoidance taskat the two highest doses tested (1.0, 2.0 mg/kg) but produced nosignificant deficits in retention. Clozapine produced no deficits in thewater maze task at the doses tested. In the step-down passive avoidanceassay animals that received the 0.25 mg/kg dose of Compound 23 showedsignificant improvement in memory compared to the vehicle group.Likewise in the modified Morris water maze, animals that received the0.03, 0.25 and the 1.0 mg/kg dose of Compound 23 showed significantimprovement in task retention compared to the vehicle group. These datashow that Compound 23 does not impair learning, but enhances learning inanimals.

[0516] Method

[0517] Non-naive male Sprague Dawley rats (SASCO St. Louis) weighingbetween 2000-300 grams, were housed in groups of three in a temperatureand humidity controlled vivarium having a 12 hour light/dark cycle.Animals had ad lib access to food and water.

[0518] Compound 23 was dissolved in 50% Polyethylene glycol (PEG) andadministered in a dose range of 0.03-1.0 mg/kg. Clozapine was dissolvedin 50% PEG and administered in a dose range of from 0.25 to 2 mg/kg.Both drugs were administered intravenously 5 minutes prior to trainingin both learning tasks.

[0519] Apparatus

[0520] Step-Down Passive Avoidance: A step-down passive avoidanceplatform 4 (cm)×7 (cm) was placed in the center of an electrified grisfloor, which was contained within a large (45×45×50 cm) whitetranslucent plexiglas enclosure having a closable lid. The bars of thegrip were spaced 1.5 cm apart and were wired to a BRS-LVE shockgenerator/scrambler which was set to deliver a 2 mA 6 second shock. Fourpassive avoidance boxes were automated by customer software (Labview)and commercial interface modules (National Instruments) connected to acomputer. The timing and delivery of the shock as well as the latency tosteo down and the number of trials taken to reach criterion duringraining was under the control of the computer. All testing was done inthe presence of 62 db white noise.

[0521] Modified Morris Water Maze: A water maze apparatus consisted of acircular tank (120 cm in diameter and 56 cm in height) having a blackinterior. The tank was surrounded by external visual cues whichconsisted of a black and white checkered wall, a black and white stripedwall, a while wall and a blue panel. The tank was filled with water(18-20° C.) to a height of 52 cm and was divided into four quadrants(North, South, East and West). A black circular plexiglas platform (withblack rubber top) was placed in the northeast quadrant approximately 1cm below the surface of the water. The submerged platform was 51 cm inheight and had a diameter of 9 cm. Training and testing was conducted inthe presence of a 62 db white noise source and under dim lightconditions.

[0522] Procedure

[0523] 1. Passive Avoidance

[0524] Acquisition Training: After pretreatment with clozapine, Compound23 or control (vehicle), the animal was placed on the platform whichautomatically started a timer. When the animal stepped off the platformit automatically received the footshock. Following each shock the animalwas removed from the box and placed in its cage for a one minuteintertrial interval and then returned to the platform. Training wasterminted when the animal remained on the platform for 120 Seconds.Immediately after training the animal was returned to its home cage in avivarium.

[0525] Retention Testing: Testing was conduced approximately 24 hoursafter training, Drug-free animals were placed on the platform in the boxin which they were trained and the latency to step down onto theunshocked floor was recorded for one trial. The animal was allowed to amaximum of 120 seconds to step down.

[0526] 2. Modified Morris Water Maze

[0527] Acquisition Training: Acquisition training in this task assayconsisted of either four or six training trials. The four trialprocedure detects cognitive enhancing effects of drugs while the sixtrial procedure detects drugs that produce learning deficits in thistask assay Compound 23 was tested in the water maze using a four rialprocedure and clozapine using a six trial training procedure. Eachanimal was placed on the platform in the tank for 20 trials separated byan intertrial interval of 2 minutes. The starting position waspseudo-randomly varied but was the same order for each animal. Duringthe ITI (intertral interval) the animal was dried off and placed near aheat source (heat lamp). The latency to reach the submeged platform oneach trial was measured and animals were allowed to remain on theplatform for 10 seconds once they reach it. Since the platform wassubmerged just below the surface of the water, the animal was requiredto use the external visual cues surrounding the tank (distal cues) tolocate the platform.

[0528] Retention Training: On the following day, each animal wasindividually tested for retention in one trial. All animals were placedin the “SOUTH” starting position and latency to find the submergedplatform was recorded.

[0529] Results

[0530] Passive Avoidance: There were no significant differences foracquisition between the vehicle group and animals treated with Compound23. Animals that received 0.25 mg/kg dose of Compound 23 remained on theplatform for a significantly longer time during retest than the vehicleanimals. Animals that received the 1.0 mg/kg and 2.0 mg/kg doses ofclozapine showed a significant deficit in acquisition compared to thevehicle group. There were no significant differences in retentionbetween clozapine treated animals and the vehicle group.

[0531] Water Maze: The difference between the first trial and the retesttrial (latency to locate the platform on the following day) revealedsignificant improvement in retention relative to controls at the 0.03mg/kd, 0.25 mg/kg and the 1.0 mg/kg dose of Compound 23. However, thedifference between the scores of trial 1 and the retest trial foranimals that received clozapine revealed no significant differences.

[0532] These results indicate that compound 23 improved memory inmammals. These results further show that compound 23 also enhanceslearning in mammals. Thus, the compounds of the invention are useful forenhancing cognition in mammals and can be used in methods for enhancingcognition, specifically learning and memory, in mammals.

[0533] The disclosures in this application of all articles andreferences, including patents, are incorporated herein by reference.

[0534] The invention and the manner and process of making and using it,are now described in such full, clear, concise and exact terms as toenable any person skilled in the art to which it pertains, to make anduse the same. It is to be understood that the foregoing describespreferred embodiments of the present invention and that modificationsmay be made therein without departing from the spirit or scope of thepresent invention as set forth in the claims. To particularly point outand distinctly claim the subject matter regarded as invention, thefollowing claims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or the pharmaceutically acceptable salts thereof wherein: R₁ is: aryl,heteroaryl, arylalkyl, cycloalkyl or naphthyl; unsubstituted orsubstituted by up to 3 substituents which may be the same or differentand represent hydrogen, halogen, trifluoromethyl, cyano, straight orbranched chain lower alkyl having 1-6 carbon atoms, hydroxy, straight orbranched chain lower alkyl having 1-6 carbon atoms, straight or branchedchain lower alkoxy having 1-6 carbon atoms, or SO₂R₉ where R₉ is NH₂ orNHCH₃; X is: N or NR₂ where R₂ is hydrogen or straight or branched chainlower alkyl having 1-6 carbon atoms. Y is: N or CR₃ Z is: CR₃ or Nprovided that Y and Z are not both CR₃; and provided that Y and Z arenot both N; R₃ is: hydrogen, lower alkyl, halogen, hydroxy lower alkylor phenyl unsubstituted or substituted by up to three substituents whichmay be the same or different and represent hydrogen, halogen,trifluoromethyl, cyano, sulfonamido, hydroxy, straight or branched chainlower alkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; R₄ is: hydrogen or straight or branchedchain lower alkyl having 1-6 carbon atoms, or R₃ and R₄ together mayrepresent —(CH₂)n₁— where n₁is 2, 3 or 4; or R₂ and R₄ together mayrepresent —(CH₂)n₂— where n₂ is 2, 3 or
 4. m is: zero, one or two R₅ andR₆ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, aryl, straight orbranched chain lower alkyl having 1-6 carbon atoms or R₂ and R₅ togethermay represent —(CH₂)n₃— where n₃ is 2 or3; or NR₅R₆ together represent:2-(1,2,3,4-tetrahydroisoquinolinyl), either unsubstituted or mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms; or NR₅R₆ represents:

where R₇ is phenyl, benzyl or phenethyl with the phenyl ringunsubstituted or substituted with up to three substituents which may bethe same or different and represent hydrogen, halogen, trifluoromethyl,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; orNR₅R₆ represents:

where p is 1, 2 or 3; W is N or CH; and W is N and R₈ is hydrogen,phenyl, pyridyl or pyrimidinyl, unsubstituted or mono or disubstitutedwith halogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms; or W is CH and R₈ is optionally substituted phenyl or anarylalkyl group such as, for example, phenylalkyl where the phenyl ringmay be substituted with up to three substituents independently selectedfrom hydrogen, halogen, trifluoromethyl, hydroxy, straight or branchedchain lower alkyl having 1-6 carbon atoms, or straight or branched chainlower alkoxy having 1-6 carbon atoms.
 2. A compound of claim 1 which is:

where R₁ is: aryl, heteroaryl, arylalkyl, cycloalkyl or naphthyl;unsubstituted or substituted by up to 3 substituents which may be thesame or different and represent hydrogen, halogen, trifluoromethyl,cyano, straight or branched chain lower alkyl having 1-6 carbon atoms,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms, orSO₂R₉ where R₉ is NH₂ or NHCH₃; R₂ is hydrogen or alkyl; R₃ is:hydrogen, lower alkyl, halogen, hydroxy lower alkyl, or phenylunsubstituted or substituted by up to three substituents independentlyselected from hydrogen, halogen, trifluoromethyl, cyano, sulfonamido,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; R₄is: hydrogen or straight or branched chain lower alkyl having 1-6 carbonatoms, or R₃ and R₄ together may represent —(CH₂)n₁— where n₁ is 2, 3 or4; or R₂ and R₄ together may represent —(CH₂)n₂— where n₂ is 2, 3 or 4.m is: zero, one or two R₅ and R₆ are the same or different and representhydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, aryl, straight or branched chain lower alkyl having 1-6 carbonatoms or R₂ and R₅ together may represent —(CH₂)n₃— where n₃ is 2 or 3;or NR₅R₆ together represent: 2-(1,2,3,4-tetrahydroisoquinolinyl), eitherunsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms; or NR₅R₆represents:

where R₇ is phenyl, benzyl or phenethyl with the phenyl ringunsubstituted or substituted with up to three substituents which may bethe same or different and represent hydrogen, halogen, trifluoromethyl,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; orNR₅R₆ represents:

where p is 1, 2, or 3; and W is N and R₈ is hydrogen, phenyl, pyridyl orpyrimidinyl, unsubstituted or mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; or Wis CH and R₈ is optionally substituted phenyl, optionally substitutedbenzoyl, or an arylalkyl group such as, for example, phenylalkyl wherethe phenyl ring may be substituted with up to three substituentsindependently selected from hydrogen, halogen, trifluoromethyl, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms.
 3. Acompound according to claim 2, wherein R₁ is phenyl optionally mono- ordisubstituted with halogen or alkoxy; R₃ is hydrogen; R₂ and R₄ arehydrogen; and R₅ is alkyl and R₆ is arylalkyl; or NR₅R₆ is:

where p is
 2. 4. A compound according to claim 2, wherein R₁ is phenyloptionally substituted with halogen or alkoxy; R₂ and R₄ are hydrogen;and NR₅R₆ is:

where p, is 2; W is N and R₈ is phenyl, pyridyl or pyrimidinyl,unsubstituted or mono or disubstituted with halogen, or straight orbranched chain lower alkoxy having 1-6 carbon atoms.
 5. A compoundaccording to claim 1, wherein NR₅R₆ represents a substituted orunsubstituted 4 aryl or heteroaryl piperidine.
 6. A compound accordingto claim 1, wherein NR₅R₆ represents a substituted or unsubstituted 4aryl or heteroaryl piperazine.
 7. A compound according to claim 1,wherein NR5R₆ represents N,N,dimethyl.
 8. A compound according to claim1, wherein R₁ is fluorine and NR₄R₅ is N,N,dimethyl.
 9. A compoundaccording to claim 1, which is selected from the group consisting of2-phenyl-4(5)-[(4-phenylpiperazin-1-yl)methyl]imidazole dihydrochloride;2-(4-fluorophenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride;2-(4-methoxyphenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride;2-phenyl-4(5)-[(4-(3-trifluoromethylphenyl)piperazin-1yl-)methyl]imidazole;2-(2-methoxyphenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride;2-(3-methoxyphenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride;2-(3-fluorophenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazole;2-(2-fluorophenyl)-4(5)[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledimaleate;2-(2-methylphenyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride;2-(5-ethyl-2-methoxyphenyl-4(5)-[(4-phenyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride;2-(5-ethyl-2-methoxyphenyl-4(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride;2-phenyl-4(5)-[(4(4-fluorophenyl)-piperazin-1yl-)methyl]imidazoledihydrochloride;2-(5-ethyl-2-methoxyphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride; and2-phenyl-4(5)-[(4(4-fluoro-2-pyrimidinyl)-piperazin-1yl)-methyl]imidazoledihydrochloride.
 10. A compound according to claim 1, which is selectedfrom the group consisting of2-(4-fluorophenyl)4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazoledihydrochloride;2-phenyl-4(5)-[(4(5-chloro-2-methylphenyl)piperazin-1yl)-methyl]imidazoledihydrochloride;2-phenyl-4(5)-[(4-(3,4-dichlorophenyl)piperazin-1yl)-methyl]-imidazole;2-phenyl-4(5)-[(4-(4-fluorophenyl)-piperidin-1yl)-methyl]imidazoledimaleate;2-(3-fluorophenyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazoledimaleate;2-(4-fluorophenyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazoledihydrochloride;2-phenyl-4(5)-[(4-(4-fluorobenzyl)-piperidin-1-yl)-methyl]-imidazoledihydrochloride;2-(2-fluorophenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(4-methylphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)methyl]-imidazole;2-(2-fluorophenyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]imidazoledimaleate;2-(4-chlorophenyl-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole;2-phenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-phenyl-4(5)-{1-[(4-benzyl-piperidin-1-yl)-ethyl)]-imidazole;2-(2-fluorophenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(4-fluorophenyl-4(5)-[(4-(4-fluoro-2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole.11. A compound according to claim 1, which is selected from the groupconsisting of1-methyl-2-phenyl-4-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazole;1-methyl-2-phenyl-5-[(4-benzyl-piperidin-1-yl)methyl]-imidazole;1-methyl-2-phenyl-5-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazole.12. A compound according to claim 1, which is selected from the groupconsisting of4-phenyl-2(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole;4-phenyl-2(5)-[(N-methyl-N-benzyl)aminomethyl]-imidazole;4-phenyl-2(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;4-phenyl-2(5)-[(4-(4-fluorobenzyl-piperidin-1-yl)-methyl]-imidazole;4-phenyl-2(5)-[(4-phenylpiperidin-1-yl)-methyl]-imidazole;4-phenyl-2(5)-[(4-(4-fluorophenyl)-piperazin-1yl-)methyl]imidazole;4-phenyl)-2(5)-[(4-(2-methoxyphenyl)-piperazin-1-yl)-methyl]imidazole;4-phenyl-2(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]imidazole;4-phenyl-2(5)-[(4-phenyl-piperazin-1yl-)methyl]imidazole;4-phenyl-2(5)-[(4-benzoyl-piperidin-1-yl)-methyl]-imidazole;4-phenyl-2(5)-[(4-(4-fluorobenzoyl-piperidin-1-yl)-methyl]-imidazole;and 5-methyl-4phenyl-2(5)-[(4-benzyl-piperidin-1-yl)-methyl]imidazoledihydrochloride
 13. A compound according to claim 1 which is selectedfrom the group consisting of2-phenyl-5-methyl-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazole;and2-phenyl-5-iodo-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)methyl]-imidazole.14. A compound according to claim 1 which is2-phenyl-4(5)-[1-((4-benzyl-piperidin-1-yl)-ethan-1-yl)]imidazole.
 15. Acompound according to claim 1 which is selected from the groupconsisting of2-(1-naphthyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole;2-(1-naphthyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(1-naphthyl)-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole;2-(1-naphthyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole;2-(2-naphthyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole;2-(2-naphthyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(2-naphthyl)-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole;and 2-(2-naphthyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole.
 16. Acompound according to claim 1, which is selected from the groupconsisting of2-(2-pyridyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole;2-(2-pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(2-pyridyl)-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole;2-(2-pyridyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole;2-(3-pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(3-pyridyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole;2-(4-pyridyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(2-quinolinyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(2-quinolinyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole;2-(2-pyrazinyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole;2-(2-pyrazinyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;and 2-(2-pyrazinyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole.
 17. Acompound according to claim 1, which is selected from the groupconsisting of2-(2-thienyl)-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole;2-(2-thienyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(2-thienyl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole; and2-(2-thienyl)-4(5)-[(4-(2-pyridyl)-piperazin-1-yl)-methyl]-imidazole.18. A compound according to claim 1, which is selected from the groupconsisting of2-(benzoyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(benzoyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;and2-(5-methoxy-3,4-dihydro-naphth-1-yl)-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole.19. A compound according to claim 1, which is selected from the groupconsisting of2-phenyl-4(5)-[(4(2-pyrimidinyl)-piperazin-1-yl)-propen-1-oyl]-imidazole;2-phenyl-4(5)-[(4-phenyl-piperazin-1-yl)-propen-1-oyl]-imidazole;2-phenyl-4(5)-[(4-hydroxy,4-(4-chlorophenyl)-piperidin-1-yl)-propen-1-oyl]-imidazole;2-phenyl-4(5)-[(4-(2pyrimidinyl)-piperazin-1-yl)-propan-1-oyl]-imidazole;2-phenyl-4(5)-[(4-phenyl-piperazin-1-yl)-propan-1-oyl]-imidazole;2-phenyl-4(5)-[(4-(2-(3,4,5,6-tetrahydro)-pyrimidinyl)-piperazin-1-yl)-propan-1-oyl]-imidazole;2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-propan-1-yl]imidazole;2-phenyl-4(5)-[(4-phenyl-piperazin-1-yl)-propan-1-yl]-imidazole; and2-phenyl-4(5)-[(4-hydroxy-4-(4-chlorophenyl)-piperidin-1-yl)-propan-1-yl]-imidazole.20. A compound according to claim 1, which is selected from the groupconsisting of2-cyclohexyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-cyclohexyl-4(5)-[(4-benzyl-piperidin-1-yl)-methyl]-imidazole;2-cyclohexyl-4(5)-[(N-methyl-N-benzyl)-methyl]-imidazole; and2-(4-methylcyclohexyl)-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole.21. A compound according to claim 1, which is selected from the groupconsisting of2,5-phenyl-4(5)-[(4-(2-pyrimidinyl)piperazin-1-yl)-methyl]-imidazole;2-(4-methylphenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-(4-iodophenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;2-phenyl-4(5)-[(4-(4-chlorophenyl)-3-methylpiperazin-1-yl)methyl]imidazole;2-phenyl-4(5)-[(4-(4-methylphenyl)-3-methylpiperazin-1-yl)methyl]imidazole;and2-phenyl-4(5)-[(4-(4-methoxyphenyl)-3-methylpiperazin-1-yl)methyl]imidazole.22. A compound according to claim 1, which is selected from the groupconsisting of2-phenyl-7-[(4-(2-pyrimidinyl)-piperazin-1-yl)-methyl]-4,5,6,7-tetrahydrobenzimidazole;2-phenyl-7-[(4-benzyl-piperidin-1-yl)-methyl]-4,5,6,7-tetrahydrobenzimidazole;and2-phenyl-7-[(N-methyl-N-benzyl)aminomethyl]-4,5,6,7-tetrahydrobenzimidazole.23. A compound according to claim 1, which is selected from the groupconsisting of2-phenyl-4(5)-[(4-(2-pyrimidinyl)-cis-2,6-dimethylpiperazin-1-yl)-methyl]-imidazole;2-phenyl-4(5)-[(4-(2-pyrimidinyl)-trans-2,5-dimethylpiperazin-1-yl)-methyl]-imidazole;and2-phenyl-4(5)-[(8-(2-pyrimidinyl)-3-8-diazabicyclo(3.2.1)octan-3-yl)-methyl]-imidazole.24. A compound according to claim 1, which is2-phenyl-4(5)-[(4-(2-pyrimidinyl)-piperazin-1-yl)-ethan-1-yl]-imidazole.25. A compound according to claim 1, which is selected from the groupconsisting of2-phenyl-4(5)-N-[(4-(2-pyrimidinyl)-piperazin-1-yl)-carboxamido]-imidazole;2-phenyl-4(5)-N-[(N-methyl-N-benzyl)-carboxamido]-imidazole;2-phenyl-4(5)-N-[(4-benzyl-piperidin-1-yl)-carboxamido]-imidazole.
 26. Acompound according to claim 1, which is5-methyl-4-phenyl-2(5)-[(4-benzyl-piperidin-1-yl)-methyl]imidazoledihydrochloride.